Compounds for treating huntington&#39;s disease

ABSTRACT

The present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington&#39;s disease.In particular, the present description relates to substituted monocyclic heteroaryl compounds of Formula (I) or Formula (II), forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington&#39;s disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 17/040,104, filed Sep. 22, 2020, which is the U.S. National Stage filing under 35 U.S.C. § 371 of International Application No. PCT/US2019/024278, filed Mar. 27, 2019, which in turn claims priority to U.S. Provisional Application No. 62/648,699, filed Mar. 27, 2018, the entire contents of which are incorporated by reference herein.

An aspect of the present description relates to compounds, forms, and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof useful for treating or ameliorating Huntington's disease. In particular, another aspect of the present description relates to substituted monocyclic heteroaryl compounds, forms and pharmaceutical compositions thereof and methods of using such compounds, forms, or compositions thereof for treating or ameliorating Huntington's disease.

BACKGROUND

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder of the brain, having symptoms characterized by involuntary movements, cognitive impairment, and mental deterioration. Death, typically caused by pneumonia or coronary artery disease, usually occurs 13 to 15 years after the onset of symptoms. The prevalence of HD is between three and seven individuals per 100,000 in populations of western European descent. In North America, an estimated 30,000 people have HD, while an additional 200,000 people are at risk of inheriting the disease from an affected parent. The disease is caused by an expansion of uninterrupted trinucleotide CAG repeats in the “mutant” huntingtin (Htt) gene, leading to production of HTT (Htt protein) with an expanded poly-glutamine (polyQ) stretch, also known as a “CAG repeat” sequence. There are no current small molecule therapies targeting the underlying cause of the disease, leaving a high unmet need for medications that can be used for treating or ameliorating HD. Consequently, there remains a need to identify and provide small molecule compounds for treating or ameliorating HD.

All other documents referred to herein are incorporated by reference into the present application as though fully set forth herein.

SUMMARY

An aspect of the present description includes compounds comprising, a compound of Formula (I) or Formula (II):

or a form thereof, wherein X, B, R₄, and n are as defined herein.

An aspect of the present description includes a method for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a method for use of a compound of Formula (I) or Formula (II) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form or composition thereof.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof in combination with an effective amount of the one or more agents.

DETAILED DESCRIPTION

An aspect of the present description relates to compounds comprising, a compound of Formula (I) or Formula (II):

-   -   or a form thereof, wherein:     -   X is CHR_(1a), C═O, O, NR_(1b), or a bond; R_(1a) is hydrogen,         halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl,         halo-C₁₋₄alkyl, amino or hydroxyl-C₁₋₄alkyl;     -   R_(1b) is hydrogen, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl         or hydroxyl-C₁₋₄alkyl; B is heterocyclyl,     -   wherein heterocyclyl is a saturated or partially unsaturated 3-7         membered monocyclic, 6-10 membered bicyclic or 13-16 membered         polycyclic ring system having 1, 2, or 3 heteroatom ring members         independently selected from N, O, or S, each optionally         substituted with 1, 2, 3, 4, or 5 substituents each selected         from R₂;     -   R₂ is independently selected from halogen, hydroxyl, cyano,         C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino,         C₁₋₄alkyl-amino, (C₁₋₆alkyl)₂-amino, halo-C₁₋₄alkyl-amino,         (halo-C₁₋₆alkyl)₂-amino, hydroxy-C₁₋₄alkyl-amino,         C₁₋₄alkoxy-C₁₋₄alkyl-amino, amino-C₁₋₄alkyl,         C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl-amino)₂-C₁₋₄alkyl,         C₁₋₄alkoxy, halo-C₁₋₄alkoxy, hydroxyl-C₁₋₄alkoxy,         C₁₋₄alkyl-C₁₋₄alkoxy, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-amino,         C₃₋₁₀cycloalkyl-amino-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl,         heteroaryl-amino, heteroaryl-C₁₋₄alkyl-amino, heterocyclyl,         heterocyclyl-C₁₋₄alkyl, heterocyclyl-amino,         heterocyclyl-amino-C₁₋₄alkyl, heterocyclyl-C₁₋₄alkoxy,         heterocyclyl-amino-C₃₋₁₀cycloalkyl, phenyl, and         phenyl-C₁₋₄alkoxy,     -   wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered         bicyclic ring system having 1, 2, 3, or 4 heteroatom ring         members independently selected from N, O, or S,     -   wherein heterocyclyl is a saturated or partially unsaturated 3-7         membered monocyclic, 6-10 membered bicyclic or 13-16 membered         polycyclic ring system having 1, 2, or 3 heteroatom ring members         independently selected from N, O, or S,     -   wherein C₃₋₁₀cycloalkyl is a saturated or partially unsaturated         3-7 membered monocyclic ring system, and     -   wherein each instance of phenyl, heteroaryl, heterocyclyl, or         C₃₋₁₀cycloalkyl is optionally substituted with 1 or 2         substituents each selected from R₃;     -   R₃ is independently selected from halogen, hydroxyl, cyano,         C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkoxy,         and halo-C₁₋₄alkoxy;     -   n is 0, 1, or 2;     -   R₄ is independently selected from halogen, hydroxyl, cyano,         C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino,         C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, C₁₋₄alkoxy,         halo-C₁₋₄alkoxy, heteroaryl, heterocyclyl, and phenyl,     -   wherein heteroaryl is a saturated 3-6 membered monocyclic or         9-10 membered bicyclic ring system having 1, 2, 3, or 4         heteroatom ring members selected from N, O, and S,     -   wherein heterocyclyl is a saturated or partially unsaturated 3-6         membered monocyclic or 9-10 membered bicyclic ring system having         1, 2, or 3 heteroatom ring members selected from N, O, and S,         and     -   wherein each instance of phenyl, heteroaryl or heterocyclyl is         optionally substituted with 1, or 2 substituents each selected         from R₅;     -   R₅ is independently selected from halogen, hydroxyl, cyano,         nitro, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino,         C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl,         hydroxyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy,         C₁₋₄alkylthio, halo-C₁₋₄alkoxy, and C₃₋₁₀cycloalkyl;     -   wherein a form of the compound is selected from the group         consisting of a salt, hydrate, solvate, racemate, enantiomer,         diastereomer, stereoisomer, and tautomer form thereof.

ASPECTS OF THE DESCRIPTION

Another aspect of the present description includes a compound of Formula (I) or Formula (II):

-   -   or a form thereof, wherein:     -   X is CHR_(1a), C═O, O, NR_(1b), or a bond;     -   R_(1a) is hydrogen, halogen, hydroxyl, cyano, C₁₋₄alkyl,         deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino or hydroxyl-C₁₋₄alkyl;     -   R_(1b) is hydrogen, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl         or hydroxyl-C₁₋₄alkyl; B is heterocyclyl,     -   wherein heterocyclyl is a saturated or partially unsaturated 3-7         membered monocyclic, 6-10 membered bicyclic or 13-16 membered         polycyclic ring system having 1, 2, or 3 heteroatom ring members         independently selected from N, O, or S, each optionally         substituted with 1, 2, 3, 4, or 5 substituents each selected         from R₂;     -   R₂ is independently selected from halogen, hydroxyl, cyano,         C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino,         C₁₋₄alkyl-amino, (C₁₋₆alkyl)₂-amino, halo-C₁₋₄alkyl-amino,         (halo-C₁₋₆alkyl)₂-amino, hydroxy-C₁₋₄alkyl-amino,         C₁₋₄alkoxy-C₁₋₄alkyl-amino, amino-C₁₋₄alkyl,         C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl-amino)₂-C₁₋₄alkyl,         C₁₋₄alkoxy, halo-C₁₋₄alkoxy, hydroxyl-C₁₋₄alkoxy,         C₁₋₄alkyl-C₁₋₄alkoxy, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-amino,         C₃₋₁₀cycloalkyl-amino-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl,         heteroaryl-amino, heteroaryl-C₁₋₄alkyl-amino, heterocyclyl,         heterocyclyl-C₁₋₄alkyl, heterocyclyl-amino,         heterocyclyl-amino-C₁₋₄alkyl, heterocyclyl-C₁₋₄alkoxy,         heterocyclyl-amino-C₃₋₁₀cycloalkyl, phenyl, and         phenyl-C₁₋₄alkoxy,     -   wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered         bicyclic ring system having 1, 2, 3, or 4 heteroatom ring         members independently selected from N, O, or S,     -   wherein heterocyclyl is a saturated or partially unsaturated 3-7         membered monocyclic, 6-10 membered bicyclic or 13-16 membered         polycyclic ring system having 1, 2, or 3 heteroatom ring members         independently selected from N, O, or S,     -   wherein C₃₋₁₀cycloalkyl is a saturated or partially unsaturated         3-7 membered monocyclic ring system, and     -   wherein each instance of phenyl, heteroaryl, heterocyclyl, or         C₃₋₁₀cycloalkyl is optionally substituted with 1 or 2         substituents each selected from R₃;     -   R₃ is independently selected from halogen, hydroxyl, cyano,         C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkoxy,         and halo-C₁₋₄alkoxy;     -   n is 0, 1, or 2;     -   R₄ is independently selected from halogen, hydroxyl, cyano,         C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino,         C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, C₁₋₄alkoxy,         halo-C₁₋₄alkoxy, heteroaryl, heterocyclyl, and phenyl,     -   wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered         bicyclic ring system having 1, 2, 3, or 4 heteroatom ring         members independently selected from N, O, or S,     -   wherein heterocyclyl is a saturated or partially unsaturated 3-6         membered monocyclic or 9-10 membered bicyclic ring system having         1, 2, or 3 heteroatom ring members selected from N, O, and S,         and     -   wherein each instance of phenyl, heteroaryl or heterocyclyl is         optionally substituted with 1, or 2 substituents each selected         from R₅;     -   R₅ is independently selected from halogen, hydroxyl, cyano,         nitro, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino,         C₁₋₆alkyl-amino, (C₁₋₆alkyl)₂-amino, amino-C₁₋₄alkyl,         hydroxyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy,         C₁₋₄alkylthio, halo-C₁₋₄alkoxy, and C₃₋₁₀cycloalkyl.

One aspect includes a compound of Formula (I) or Formula (II), wherein X is selected from CHR_(1a), C═O, O, NR_(1b), and a bond.

Another aspect includes a compound of Formula (I) wherein X is CHR_(1a).

Another aspect includes a compound of Formula (I) or Formula (II) wherein X is C═O.

Another aspect includes a compound of Formula (I) or Formula (II) wherein X is O.

Another aspect includes a compound of Formula (I) or Formula (II) wherein X is NR_(1b).

Another aspect includes a compound of Formula (I) or Formula (II) wherein X is a bond.

One aspect includes a compound of Formula (I) or Formula (II), wherein R_(1a) is selected from hydrogen, halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, and hydroxyl-C₁₋₄alkyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1a) is selected from hydrogen, cyano, C₁₋₄alkyl, and amino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1a) is hydrogen.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1a) is cyano.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1a) is C₁₋₄alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1a) methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1a) is amino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1b) is selected from hydrogen and C₁₋₄alkyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1b) is hydrogen.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1b) is C₁₋₄alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R_(1b) is methyl.

One aspect includes a compound of Formula (I) or Formula (II), wherein B is heterocyclyl,

-   -   wherein heterocyclyl is a saturated or partially unsaturated 3-7         membered monocyclic, 6-10 membered bicyclic or 13-16 membered         polycyclic ring system having 1, 2, or 3 heteroatom ring members         independently selected from N, O, or S, each optionally         substituted with 1, 2, 3, 4, or 5 substituents each selected         from R₂.

Another aspect includes a compound of Formula (I) or Formula (II), wherein B is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydrocyclopentapyrrol-(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4-c′]dipyrrol-(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, 5-azaspiro[2.4]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, (1R,5S)-8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-en-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-yl, 9-azabicyclo[3.3.1]nonanyl, (1R,5S)-9-azabicyclo[3.3.1]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[3.2.2]nonanyl, azaspiro[3.3]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 1,7,-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 5,8-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 6,9-diazaspiro[4.5]decyl, 6-oxa-2,9-diazaspiro[4.5]decanyl, 2,9-diazaspiro[5.5]undecanyl, and 7-azadispiro[5.1.5⁸.3⁶]hexadecanyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R₂.

Another aspect includes a compound of Formula (I) or Formula (II), wherein B is heterocyclyl selected from pyrrolidinyl, piperidinyl, piperazinyl, hexahydrocyclopentapyrrol-(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, 5-azaspiro[2.4]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 9-azabicyclo[3.3.1]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 1,7,-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 6-oxa-2,9-diazaspiro[4.5]decanyl, and 2,9-diazaspiro[5.5]undecanyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R₂.

Another aspect includes a compound of Formula (I) or Formula (II), wherein B is heterocyclyl selected from pyrrolidinyl, piperidinyl, and 2,7-diazaspiro[3.5]nonanyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R₂.

Another aspect includes a compound of Formula (I) or Formula (II), wherein B is heterocyclyl selected from azetidin-1-yl, tetrahydrofuran-3-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, 1,4-diazepan-1-yl, 1,2-dihydropyridin-2-yl, 1,2-dihydropyridin-3-yl, 1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl, 1,2-dihydropyridin-6-yl, 1,2,5,6-tetrahydropyridin-5-yl, 1,2,3,6-tetrahydropyridin-4-yl, hexahydrocyclopentapyrrol-2(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-1(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-5(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl, octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl, octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4-c′]dipyrrol-2(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazin-2-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 5-azaspiro[2.4]heptan-5-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 8-azabicyclo[3.2.1]octan-3-yl, (1R,5S)-8-azabicyclo[3.2.1]octan-3-yl, 8-azabicyclo[3.2.1]oct-2-en-3-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl, 9-azabicyclo[3.3.1]nonan-3-yl, (1R,5S)-9-azabicyclo[3.3.1]nonan-3-yl, 2,5-diazabicyclo[2.2.1]heptan-2-yl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 1,4-diazabicyclo[3.1.1]heptan-4-yl, 3,6-diazabicyclo[3.2.0]heptan-3-yl, 3,6-diazabicyclo[3.2.0]heptan-6-yl, 2,5-diazabicyclo[2.2.2]octan-2-yl, 1,4-diazabicyclo[3.2.1]octan-4-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, (1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl, 1,4-diazabicyclo[3.2.2]nonan-4-yl, azaspiro[3.3]heptan-2-yl, 4,7-diazaspiro[2.5]octan-4-yl, 4,7-diazaspiro[2.5]octan-7-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.4]octan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 1,7,-diazaspiro[4.4]nonan-1-yl, 1,7,-diazaspiro[4.4]nonan-7-yl, 1,7-diazaspiro[3.5]nonan-7-yl, 2,6-diazaspiro[3.5]nonan-2-yl, 2,6-diazaspiro[3.5]nonan-6-yl, 1,7-diazaspiro[3.5]nonan-7-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 5,8-diazaspiro[3.5]nonan-8-yl, 2,7-diazaspiro[4.4]nonan-2-yl, 2,7-diazaspiro[4.5]decan-2-yl, 2,7-diazaspiro[4.5]decan-7-yl, 2,8-diazaspiro[4.5]decan-8-yl, 6,9-diazaspiro[4.5]dec-9-yl, 6-oxa-2,9-diazaspiro[4.5]decan-2-yl, 2,9-diazaspiro[5.5]undecan-9-yl, and 7-azadispiro[5.1.5⁸.3⁶]hexadecan-15-yl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R₂.

Another aspect includes a compound of Formula (I) or Formula (II), wherein B is heterocyclyl selected from pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-4-yl, piperazin-1-yl, hexahydrocyclopentapyrrol-2(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl, octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl, octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, 5-azaspiro[2.4]heptan-5-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 3-azabicyclo[3.1.0]hexan-3-yl, 8-azabicyclo[3.2.1]octan-3-yl, 9-azabicyclo[3.3.1]nonan-3-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.4]octan-6-yl, 1,7,-diazaspiro[4.4]nonan-7-yl, 1,7-diazaspiro[3.5]nonan-7-yl, 2,6-diazaspiro[3.5]nonan-2-yl, 1,7-diazaspiro[3.5]nonan-7-yl, 2,7-diazaspiro[3.5]nonan-2-yl, 2,7-diazaspiro[3.5]nonan-7-yl, 2,7-diazaspiro[4.4]nonan-2-yl, 2,7-diazaspiro[4.5]decan-2-yl, 2,8-diazaspiro[4.5]decan-8-yl, 6-oxa-2,9-diazaspiro[4.5]decan-2-yl, and 2,9-diazaspiro[5.5]undecan-9-yl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R₂.

Another aspect includes a compound of Formula (I) or Formula (II), wherein B is heterocyclyl selected from pyrrolidin-1-yl, pyrrolidin-3-yl, piperidin-4-yl, 2,7-diazaspiro[3.5]nonan-2-yl, and 2,7-diazaspiro[3.5]nonan-7-yl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R₂.

One aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is selected from halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₆alkyl)₂-amino, halo-C₁₋₄alkyl-amino, (halo-C₁₋₆alkyl)₂-amino, hydroxy-C₁₋₄alkyl-amino, C₁₋₄alkoxy-C₁₋₄alkyl-amino, amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl-amino)₂-C₁₋₄alkyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, hydroxyl-C₁₋₄alkoxy, C₁₋₄alkyl-C₁₋₄alkoxy, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-amino, C₃₋₁₀cycloalkyl-amino-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl, heteroaryl-amino, heteroaryl-C₁₋₄alkyl-amino, heterocyclyl, heterocyclyl-C₁₋₄alkyl, heterocyclyl-amino, heterocyclyl-amino-C₁₋₄alkyl, heterocyclyl-C₁₋₄alkoxy, heterocyclyl-amino-C₃₋₁₀cycloalkyl, phenyl, and phenyl-C₁₋₄alkoxy,

-   -   wherein heteroaryl is a saturated 3-7 membered monocyclic, 6-10         membered bicyclic or 13-16 membered polycyclic ring system         having 1, 2, 3, or 4 heteroatom ring members independently         selected from N, O, or S,     -   wherein heterocyclyl is a saturated or partially unsaturated 3-7         membered monocyclic, 6-10 membered bicyclic or 13-16 membered         polycyclic ring system having 1, 2, or 3 heteroatom ring members         independently selected from N, O, or S,     -   wherein C₃₋₁₀cycloalkyl is a saturated or partially unsaturated         3-7 membered monocyclic ring system, and     -   wherein each instance of phenyl, heteroaryl, heterocyclyl, or         C₃₋₁₀cycloalkyl is optionally substituted with 1 or 2         substituents each selected from R₃.

One aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is selected from halogen, hydroxyl, C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₆alkyl)₂-amino, halo-C₁₋₄alkyl-amino, hydroxy-C₁₋₄alkyl-amino, C₁₋₄alkoxy-C₁₋₄alkyl-amino, C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl-amino)₂-C₁₋₄alkyl, C₁₋₄alkoxy, C₃₋₁₀cycloalkyl-amino, C₃₋₁₀cycloalkyl-amino-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl-amino, heterocyclyl-amino, heterocyclyl-amino-C₁₋₄alkyl, and heterocyclyl-amino-C₃₋₁₀cycloalkyl,

-   -   wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered         bicyclic ring system having 1, 2, 3, or 4 heteroatom ring         members independently selected from N, O, or S,     -   wherein heterocyclyl is a saturated or partially unsaturated 3-7         membered monocyclic, 6-10 membered bicyclic or 13-16 membered         polycyclic ring system having 1, 2, or 3 heteroatom ring members         independently selected from N, O, or S,     -   wherein C₃₋₁₀cycloalkyl is a saturated or partially unsaturated         3-7 membered monocyclic ring system, and     -   wherein each instance of heteroaryl, heterocyclyl, or         C₃₋₁₀cycloalkyl is optionally substituted with 1 or 2         substituents each selected from R₃.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is halogen selected from bromo, chloro, fluoro, and iodo.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is fluoro.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is hydroxyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₁₋₄alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₁₋₄alkyl selected from methyl or ethyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is ethyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is amino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₁₋₆alkyl-amino, wherein C₁₋₆alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl, and 3-methylpentyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₁₋₆alkyl-amino, wherein C₁₋₆alkyl is selected from methyl, ethyl, isopropyl, tert-butyl, 2-methylbutyl, and 3-methylpentyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is methylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is ethylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is isopropylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is tert-butylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is 2-methylbutyl-2-amino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is 3-methylpentyl-3-amino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is (C₁₋₆alkyl)₂-amino, wherein C₁₋₄alkyl is each independently selected from selected from methyl, ethyl, isopropyl, tert-butyl, 2-methylbutyl, and 3-methylpentyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is (C₁₋₆alkyl)₂-amino, wherein C₁₋₄alkyl is methyl or ethyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is dimethylamino or diethylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is dimethylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is diethylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is halo-C₁₋₄alkyl-amino, wherein C₁₋₄alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, partially or completely substituted with one or more halogen atoms where allowed by available valences.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is halo-C₁₋₄alkyl-amino, wherein C₁₋₄alkyl is selected from isopropyl and tert-butyl, partially or completely substituted with one or more halogen atoms where allowed by available valences.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is 1-fluoro-2-methylpropan-2-amino or 1-fluoropropan-2-amino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is hydroxy-C₁₋₄alkyl-amino, wherein C₁₋₄alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl, partially or completely substituted with one or more hydroxy groups where allowed by available valences.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is hydroxy-C₁₋₄alkyl-amino, wherein C₁₋₄alkyl is selected from ethyl and propyl, partially or completely substituted with one or more hydroxy groups where allowed by available valences.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is 2-hydroxyethylamino or 3-hydroxypropylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₁₋₄alkoxy-C₁₋₄alkyl-amino, wherein C₁₋₄alkoxy is selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy, and C₁₋₄alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₁₋₄alkoxy-C₁₋₄alkyl-amino, wherein C₁₋₄alkoxy is methoxy and C₁₋₄alkyl is selected propyl, isopropyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is 1-methoxypropan-2-amino or 1-methoxy-2-methylpropan-2-amino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₁₋₄alkyl-amino-C₁₋₄alkyl, wherein each C₁₋₄alkyl is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₁₋₄alkyl-amino-C₁₋₄alkyl, wherein each C₁₋₄alkyl is independently selected from methyl, ethyl, isopropyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is methylaminomethyl, propan-2-yl-aminomethyl, propan-2-yl-aminoethyl, or tert-butylaminomethyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is (C₁₋₄alkyl-amino)₂-C₁₋₄alkyl, wherein each C₁₋₄alkyl is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is (C₁₋₄alkyl-amino)₂-C₁₋₄alkyl, wherein each C₁₋₄alkyl is methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is dimethylaminomethyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₁₋₄alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ methoxy.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₃₋₁₀cycloalkyl-amino, wherein C₃₋₁₀cycloalkyl is selected from cyclopropyl, cylcobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]hexanyl, and adamantyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₃₋₁₀cycloalkyl-amino, wherein C₃₋₁₀cycloalkyl is selected from cyclopropyl, cylcobutyl, cyclopentyl, bicyclo[2.2.1]hexanyl, and adamantyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₃₋₁₀cycloalkyl-amino-C₁₋₄alkyl, wherein C₃₋₁₀cycloalkyl is selected from cyclopropyl, cylcobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]hexanyl, and adamantyl and C₁₋₄alkyl is selected from methyl, ethyl, propyl, and butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is C₃₋₁₀cycloalkyl-amino-C₁₋₄alkyl, wherein C₃₋₁₀cycloalkyl is selected from cyclopropyl, cylcobutyl, and cyclopentyl, and C₁₋₄alkyl is methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is cyclopropylaminomethyl, cyclobutylaminomethyl, or cyclopentylaminomethyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is heteroaryl-C₁₋₄alkyl-amino, wherein heteroaryl is selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 9H-purinyl, quinolinyl, isoquinolinyl, and quinoxalinyl, and C₁₋₄alkyl is selected from methyl, ethyl, propyl, and butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is heteroaryl-C₁₋₄alkyl-amino, wherein heteroaryl is pyridinyl, and C₁₋₄alkyl is methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is pyridin-2-yl-methylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is heterocyclyl-amino, wherein heterocyclyl is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, 8-azabicyclo[3.2.1]octanyl, and 8-oxabicyclo[3.2.1]octanyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is heterocyclyl-amino, wherein heterocyclyl is selected from oxetanyl and tetrahydropyranyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is oxetanylamino or tetrahyropyranylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is heterocyclyl-amino-C₁₋₄alkyl, wherein heterocyclyl is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxanyl, 8-azabicyclo[3.2.1]octanyl, and 8-oxabicyclo[3.2.1]octanyl, and C₁₋₄alkyl is selected from methyl, ethyl, propyl, and butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is heterocyclyl-amino-C₁₋₄alkyl, wherein heterocyclyl is selected from tetrahydrofuranyl, oxanyl, and 8-oxabicyclo[3.2.1]octanyl, and C₁₋₄alkyl is methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is oxanylaminomethyl, tetrahydrofuranylaminomethyl, and 8-oxabicyclo[3.2.1]octanylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is heterocyclyl-amino-C₃₋₁₀cycloalkyl, wherein heterocyclyl is selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxanyl, 8-azabicyclo[3.2.1]octanyl, and 8-oxabicyclo[3.2.1]octanyl, and C₃₋₁₀cycloalkyl is selected from cyclopropyl, cylcobutyl, cyclopentyl, and cyclohexyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is heterocyclyl-amino-C₃₋₁₀cycloalkyl, wherein heterocyclyl is oxanyl, and C₃₋₁₀cycloalkyl is cyclopropyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₂ is oxanylaminocyclopropyl.

One aspect includes a compound of Formula (I) or Formula (II), wherein R₃ is halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkoxy, and halo-C₁₋₄alkoxy.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₃ is halogen and C₁₋₄alkyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₃ is halogen selected from bromo, chloro, fluoro, and iodo.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₃ is fluoro.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₃ is C₁₋₄alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₃ is methyl.

One aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is selected from halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, heteroaryl, heterocyclyl, and phenyl,

-   -   wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered         bicyclic ring system having 1, 2, 3, or 4 heteroatom ring         members independently selected from N, O, or S, wherein         heterocyclyl is a saturated or partially unsaturated 3-6         membered monocyclic or 9-10 membered bicyclic ring system having         1, 2, or 3 heteroatom ring members selected from N, O, and S,         and     -   wherein each instance of phenyl, heteroaryl or heterocyclyl is         optionally substituted with 1 or 2 substituents each selected         from R₅.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is selected from halogen, C₁₋₄alkoxy, heteroaryl, and phenyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is halogen selected from bromo, chloro, fluoro, and iodo.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is fluoro.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is C₁₋₄alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ methoxy.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is heteroaryl,

-   -   wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered         bicyclic ring system having 1, 2, 3, or 4 heteroatom ring         members independently selected from N, O, or S, optionally         substituted with 1 or 2 substituents each selected from R₅.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyridin-2(1H)-on-yl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyridazinyl, pyridazin-3(2H)-on-yl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1,3-oxazolo[5,4-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridin-yl, pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridin-yl, 5H-pyrrolo[2,3-b]pyrazinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, quinolinyl, isoquinolinyl, and quinoxalinyl, optionally substituted with 1 or 2 substituents each selected from R₅.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 2H-tetrazolyl, pyridinyl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyridazinyl, pyridazin-3(2H)-on-yl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1H-indazolyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 1,3-oxazolo[5,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, and quinolinyl, optionally substituted with 1 or 2 substituents each selected from R₅.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is heteroaryl selected from thien-2-yl, thien-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1H-1,2,3-triazol-1-yl, 1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2(1H)-on-4-yl, pyridin-2(1H)-on-5-yl, pyridin-2(1H)-on-6-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-4(3H)-on-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-3(2H)-on-5-yl, 1,2,4-triazin-3-yl, 1,3,5-triazin-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indazol-5-yl, 2H-indazol-5-yl, indolizin-2-yl, benzofuran-2-yl, benzofuran-5-yl, benzothien-2-yl, benzothien-3-yl, 1H-benzimidazol-2-yl, 1H-benzimidazol-5-yl, 1H-benzimidazol-6-yl, 1,3-benzoxazol-2-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzothiazol-2-yl, 1,3-benzothiazol-5-yl, 1,3-benzothiazol-6-yl, 1,3-benzodioxol-5-yl, 1,2,3-benzotriazol-5-yl, 9H-purin-8-yl, furo[3,2-b]pyridin-2-yl, furo[3,2-c]pyridin-2-yl, furo[2,3-c]pyridin-2-yl, 1,3-oxazolo[5,4-b]pyridine-5-yl, thieno[3,2-c]pyridin-2-yl, thieno[2,3-d]pyrimidin-6-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-c]pyridin-4-yl, pyrrolo[1,2-a]pyrimidin-7-yl, pyrrolo[1,2-a]pyrazin-7-yl, pyrrolo[1,2-b]pyridazin-2-yl, pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyrazin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-c]pyridin-1-yl, 1H-pyrazolo[3,4-c]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrazolo[4,3-d]pyrimidin-5-yl, 2H-pyrazolo[4,3-b]pyridin-5-yl, 2H-pyrazolo[4,3-c]pyridin-5-yl, 5H-pyrrolo[2,3-b]pyrazin-2-yl, pyrazolo[1,5-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyrimidin-2-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-c]pyrimidin-2-yl, imidazo[1,2-b]pyridazin-2-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyrazin-6-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-5-yl, imidazo[2,1-b][1,3]thiazol-6-yl, imidazo[2,1-b][1,3,4]thiadiazol-6-yl, [1,3]oxazolo[4,5-b]pyridin-2-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, tetrazolo[1,5-a]pyridin-7-yl, tetrazolo[1,5-b]pyridazin-7-yl, quinolin-6-yl, isoquinolin-6-yl, and quinoxalin-2-yl, optionally substituted with 1 or 2 substituents each selected from R₅.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is heteroaryl selected from thien-2-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1,3-thiazol-2-yl, 1,3-thiazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-thiadiazol-5-yl, 1H-1,2,3-triazol-4-yl, 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol-1-yl, 2H-tetrazol-2-yl, 2H-tetrazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-4(3H)-on-6-yl, pyridazin-3-yl, pyridazin-4-yl, pyridazin-3(2H)-on-5-yl, 1,2,4-triazin-3-yl, 1,3,5-triazin-2-yl, 1H-indazol-5-yl, 1H-benzimidazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzodioxol-5-yl, 1,2,3-benzotriazol-5-yl, 1,3-oxazolo[5,4-b]pyridine-5-yl, 1H-pyrazolo[3,4-b]pyrazin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-6-yl, 1H-pyrazolo[3,4-c]pyridin-1-yl, 1H-pyrazolo[3,4-c]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-5-yl, 1H-pyrazolo[4,3-b]pyridin-6-yl, 1H-pyrazolo[4,3-d]pyrimidin-5-yl, 5H-pyrrolo[2,3-b]pyrazin-2-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-b]pyridazin-6-yl, imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyrazin-6-yl, 1H-imidazo[4,5-b]pyridin-5-yl, 3H-imidazo[4,5-b]pyridin-5-yl, [1,2,3]triazolo[1,5-a]pyridin-5-yl, [1,2,3]triazolo[1,5-a]pyridin-6-yl, 1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl, tetrazolo[1,5-a]pyridin-7-yl, tetrazolo[1,5-b]pyridazin-7-yl, quinolin-6-yl, and isoquinolin-6-yl, optionally substituted with 1 or 2 substituents each selected from R₅.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₄ is phenyl, 1 or 2 substituents each selected from R₅.

One aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is selected from halogen, hydroxyl, cyano, nitro, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, C₁₋₄alkylthio, halo-C₁₋₄alkoxy, and C₃₋₁₀cycloalkyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is selected from halogen, hydroxyl, cyano, nitro, C₁₋₄alkyl, deutero-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, C₁₋₄alkylthio, and C₃₋₁₀cycloalkyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is halogen selected from bromo, chloro, fluoro, and iodo.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is halogen selected from bromo, chloro and fluoro.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is chloro.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is fluoro.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is hydroxy.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is cyano.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is nitro.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is C₁₋₄alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is deutero-C₁₋₄alkyl wherein C₁₋₄alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl partially or completely substituted with one or more deuterium atoms where allowed by available valences.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is (²H3)methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is amino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is C₁₋₆alkyl-amino wherein C₁₋₆alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 2-methylbutyl, and 3-methylpentyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is C₁₋₄alkyl-amino wherein C₁₋₄alkyl is methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is methylamino.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is amino-C₁₋₄alkyl wherein C₁₋₄alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is amino-C₁₋₄alkyl wherein C₁₋₄alkyl is methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is aminomethyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is hydroxyl-C₁₋₄alkyl, wherein C₁₋₄alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl partially or completely substituted with one or more hydroxyl groups where allowed by available valences.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is hydroxyl-C₁₋₄alkyl, wherein C₁₋₄alkyl is methyl substituted with one hydroxyl group.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is hydroxymethyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is C₁₋₄alkyl-carbonyl, wherein C₁₋₄alkyl is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is C₁₋₄alkyl-carbonyl, wherein C₁₋₄alkyl is methyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is CH₃C(O)—.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is C₁₋₄alkoxy selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ methoxy.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is C₁₋₄alkylthio selected from methylthio, ethylthio, propylthio, isopropylthio, butylthio, and tert-butylthio.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ methylthio.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is C₃₋₁₀cycloalkyl selected from cyclopropyl, cylcobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]hexanyl, and adamantyl.

Another aspect includes a compound of Formula (I) or Formula (II), wherein R₅ is cyclopropyl.

Another aspect of the compound of Formula (I) or Formula (II) includes the compound of Formula (I):

or a form thereof.

Another aspect of the compound of Formula (I) or Formula (II) includes the compound of Formula (II):

or a form thereof.

An aspect of the compound of Formula (I) or Formula (II) or a form thereof includes a compound selected from the group consisting of:

-   -   wherein a form of the compound is selected from the group         consisting of a salt, hydrate, solvate, racemate, enantiomer,         diastereomer, stereoisomer, and tautomer form thereof.

An aspect the compound of Formula (I) or Formula (II) or a form thereof (wherein compound number (#¹) indicates that the salt form was isolated) includes a compound selected from the group consisting of:

Cpd Name   1¹ 5-(5-methyl-1,3-oxazol-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   2¹ 5-(6-methoxypyrimidin-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   3¹ 5-(2-methoxypyridin-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  4 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H-1,2,3- triazol-4-yl)phenol  5 4-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino}-1,2,4-triazin-6- yl}phenyl)pyridin-2-ol   6¹ 5-(3-methyl-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  7 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,3- oxazol-2-yl)phenol  8 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(pyridin- 4-yl)phenol  9 5-(2-methylpyridin-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol   10¹ 5-(4-methyl-1H-imidazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   11¹ 5-(1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4-triazin-6- yl}phenol   12¹ 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   13¹ 5-(1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol   14¹ 5-[1-(²H₃)methyl-1H-pyrazol-4-yl]-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol   15¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol   16¹ 5-(1-methyl-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino1- 1,2,4-triazin-6-yl}phenol   17¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-1-yl)phenol   18¹ 5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol   19¹ 2-{3-[methyl(piperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol   20¹ 2-{3-[methyl(piperidin-3-yl)amino]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol  21 2-(3-{[(1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol  22 2-(3-{[(1R,3S,5S)-9-azabicyclo[3.3.1]nonan-3-yl](methyl)amino}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol   23¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2-methyl- 2H-1,2,3-triazol-4-yl)phenol   24¹ 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(1H- pyrazol-4-yl)phenol  25 (6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)-1,2,4-triazin-3-yl)(2,2,6,6- tetramethylpiperidin-4-yl)methanone  26 (3-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)-1,2,4-triazin-6-yl)(2,2,6,6- tetramethylpiperidin-4-yl)methanone  27 2-(6-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)-1,2,4-triazin-3-yl)-2-(2,2,6,6- tetramethylpiperidin-4-yl)acetonitrile  28 2-(3-(2-hydroxy-4-(1H-pyrazol-4-yl)phenyl)-1,2,4-triazin-6-yl)-2-(2,2,6,6- tetramethylpiperidin-4-yl)acetonitrile  29 2-(3-(amino(2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol  30 2-(6-(amino(2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,2,4-triazin-3-yl)-5-(1H- pyrazol-4-yl)phenol  31 2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)-5-(1,3,5- triazin-2-yl)phenol  32 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-3-yl)-5-(1,3,5- triazin-2-yl)phenol   33¹ 4-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)-1,3,5-triazin-2-ol  34 4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-3- yl)phenyl)-1,3,5-triazin-2-ol  35 5-(4-amino-1,3,5-triazin-2-yl)-2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)- 1,2,4-triazin-6-yl)phenol  36 5-(4-amino-1,3,5-triazin-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)- 1,2,4-triazin-3-yl)phenol  37 5-(4-chloro-1,3,5-triazin-2-yl)2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)- 1,2,4-triazin-6-yl)phenol  38 5-(4-chloro-1,3,5-triazin-2-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)- 1,2,4-triazin-3-yl)phenol  39 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-3-yl)-5-(5-methyl- 1H-pyrazol-4-yl)phenol  40 5-(5-chloro-1H-pyrazol-4-yl)-2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)- 1,2,4-triazin-6-yl)phenol  41 5-(5-chloro-1H-pyrazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)- 1,2,4-triazin-3-yl)phenol  42 4-(3-hydroxy-4-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6- yl)phenyl)-1H-pyrazole-5-carbonitrile  43 4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-3- yl)phenyl)-1H-pyrazole-5-carbonitrile  44 5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,2,4-triazin-6-yl)phenol  45 5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,2,4-triazin-3-yl)phenol  46 5-(5-chloro-1-methyl-1H-pyrazol-4-yl)-2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,2,4-triazin-6-yl)phenol  47 5-(5-chloro-l-methyl-1H-pyrazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,2,4-triazin-3-yl)phenol  48 4-(3-hydroxy-4-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6- yl)phenyl)-1-methyl-1H-pyrazole-5-carbonitrile  49 4-(3-hydroxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-3- yl)phenyl)-1-methyl-1H-pyrazole-5-carbonitrile   50¹ 5-(4-fluoro-1H-imidazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   51¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(3-methyl- 1H-1,2,4-triazol-1-yl)phenol   52¹ 2-{3-[(1-methylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol  53 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(thiophen- 2-yl)phenol  54 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(4- methylthiophen-2-yl)phenol   55¹ 5-(4-methoxy-1H-pyrazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol  56 4-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino1-1,2,4-triazin-6- yl}phenyl)-1-methylpyridin-2(1H)-one   57¹ 5-(3-chloro-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   58¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,3- thiazol-2-yl)phenol   59¹ 5-(4-chloro-1H-imidazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   60¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (pyridazin-4-yl)phenol   61¹ 5-(6-methylpyridazin-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   62¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1-methyl- 1H-1,2,4-triazol-3-yl)phenol   63¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2H-1,2,3- triazol-2-yl)phenol  64 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2-methyl- 1,3-thiazol-5-yl)phenol   65¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,2,4- thiadiazol-5-yl)phenol   66¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(3-methyl- 1,2,4-thiadiazol-5-yl)phenol   67¹ 2-{3-[(3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)(methyl)amino]-1,2,4-triazin-6-yl}-5- (1H-pyrazol-4-yl)phenol   68¹ 1-[1-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin- 6-yl}phenyl)-1H-pyrazol-4-yl]ethan-l-one   69¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(4-methyl- 2H-1,2,3-triazol-2-yl)phenol  70 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(pyridin- 3-yl)phenol   71¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(pyridin- 2-yl)phenol   72¹ 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4- triazin-6-yl}phenol   73¹ 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol   74¹ 5-(2-methyl-1,3-oxazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   75¹ 5-(1-methyl-1H-imidazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   76¹ 5-(1-methyl-1H-pyrazol-3-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   77¹ 2-{3-{[(1R,3s,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]amino}-1,2,4-triazin-6-yl)- 5-(1H-pyrazol-4-yl)phenol  78 2-{3-{[1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]amino}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol   79¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H-1,2,4- triazol-1-yl)phenol   80¹ 5-(imidazo[1,2-a]pyrazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   81¹ 5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol   82¹ 2-{3-[(2,6-dimethylpiperidin-4-yl)oxy]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol  83 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(pyrazin- 2-yl)phenol   84¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (pyridazin-3-yl)phenol  85 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (pyrimidin-2-yl)phenol   86¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (pyrimidin-5-yl)phenol  87 2-(3-{methyl[(1R,3s,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl]amino}-1,2,4-triazin- 6-yl)-5-(1H-pyrazol-4-yl)phenol   88¹ 5-(4-methoxy-1,3,5-triazin-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol   89¹ 5-(1H-imidazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol   90¹ 1-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)-1H-pyrazol-4-ol   91¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,3- oxazol-5-yl)phenol   92¹ 5-(imidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol   93¹ 5-(4-fluoro-1H-pyrazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   94¹ 5-(4-methyl-1H-pyrazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol   95¹ 2-[3-(2,7-diazaspiro[3.5]nonan-7-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol   96¹ 2-[3-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol   97¹ 5-(1H-indazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  98 5-(4-fluoropyridin-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol   99¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(4-nitro- 2H-1,2,3-triazol-2-yl)phenol 100 2-[3-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol  101¹ 5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol  102¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (pyrimidin-4-yl)phenol  103¹ 4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}[1,1'- biphenyl]-3,4’-diol 104 5-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)pyridin-2(1H)-one  105¹ 6-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}quinolin-7-ol 106 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,3,4- oxadiazol-2-yl)phenol  107¹ 5-(1H-pyrazol-3-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4-triazin-6- yl}phenol  108¹ 5-(1-methyl-1H-pyrazol-3-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4- triazin-6-yl}phenol  109¹ 2-[3-(2,6-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  110¹ 2-[3-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  111¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-3-yl)phenol  112¹ 5-(5-fluoropyrimidin-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  113¹ 2-[3-(1-methyl-1,7-diazaspiro[3.5]nonan-7-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol  114¹ 2-{3-[(3S)-3-(methylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol  115¹ 2-{3-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol  116¹ 2-{3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol  117¹ 2-{3-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-1,2,4-triazin-6-yl}- 5-(1H-pyrazol-4-yl)phenol  118¹ 2-[3-(2,6-diazaspiro[3.3]heptan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  119¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(5-methyl- 2H-tetrazol-2-yl)phenol  120¹ 2-{3-[(2R,4s,6S)-2,6-diethylpiperidin-4-yl]oxy}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  121¹ 2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2H-1,2,3-triazol- 2-yl)phenol  122¹ 2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4-triazin-6-yl}-5-(2H-1,2,3-triazol-2- yl)phenol  123¹ 5-(6-chloropyridazin-3-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  124¹ 5-(1-methyl-1H-pyrazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol 125 4-fluoro-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (1H-pyrazol-5-yl)phenol  126¹ 2-{3-[(3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol  127¹ 2-{3-[6-(diethylamino)-3-azabicyclo[3.1.0]hexan-3-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol  128¹ 5-(5-methylpyrimidin-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  129¹ 5-(4-methylpyrimidin-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  130¹ 5-(2-chloropyrimidin-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol 131 5-(1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  132¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[3,4-b]pyridin-5-yl)phenol  133¹ 5-(3-chloro-1H-1,2,4-triazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol  134¹ 6-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)pyridazin-3-ol 135 1-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)-1H-pyrazole-4-carbonitrile 136 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[4,3-b]pyridin-5-yl)phenol 137 2-{3-[3-(cyclopropylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol 138 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol 139 1-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)-1H-imidazole-4-carbonitrile  140¹ 1-[1-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin- 6-yl}phenyl)-1H-imidazol-4-yl]ethan-l-one  141¹ 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  142¹ 5-(2-methylimidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]-1,2,4-triazin-6-yl}phenol  143¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2-methyl- 2H-tetrazol-5-yl)phenol 144 5-(6-methoxy-1,2,4-triazin-3-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol 145 5-(1,3-benzoxazol-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  146¹ 6-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)-3-methylpyrimidin-4(3H)-one  147¹ 5-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)-2-methylpyridazin-3(2H)-one  148¹ 2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol 149 5-(3-fluoro-1H-pyrazol-4-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol 150 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[(3aS,7aR)-octahydro-5H-pyrrolo[3,2-c]pyridin-5- yl]-1,2,4-triazin-6-yl}phenol  151¹ 2-[3-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(3-fluoro-1H-pyrazol-4- yl)phenol  152¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- ([1,2,3]triazolo[1,5-a]pyridin-5-yl)phenol  153¹ 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[(3aS,7aR)-1-methyloctahydro-5H-pyrrolo[3,2- c]pyridin-5-yl]-1,2,4-triazin-6-yl}phenol 154 2-(3-{3-[(2-methylbutan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol  155¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (tetrazolo[1,5-a]pyridin-7-yl)phenol  156¹ 5-(4-fluoro-1H-pyrazol-3-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  157¹ 2-(3-{3-[(adamantan-1-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  158¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(5H- pyrrolo[2,3-b]pyrazin-2-yl)phenol  159¹ 2-(3-{3-[(adamantan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  160¹ 2-(3-{3-[(3,5-dimethyladamantan-1-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol  161¹ 5-[4-(hydroxymethyl)-1H-pyrazol-1-yl]-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol  162¹ 2-{3-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-1,2,4- triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol 163 5-(3-methyl-3H-imidazo[4,5-b]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  164¹ 5-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  165¹ 2-{3-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]-1,2,4-triazin-6- yl}-5-(1H-pyrazol-4-yl)phenol  166¹ 2-[3-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol  167¹ 2-{3-[(3aR,4S,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-1,2,4- triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol  168¹ 3-amino-6-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenyl)-4-methylpyridin-2-ol  169¹ 5-(2,7-dimethyl[1,3]oxazolo[5,4-b]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol 170 2-(3-{3-[(3-methylpentan-3-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol 171 2-{3-[4-(tert-butylamino)-2-methylpyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol- 4-yl)phenol  172¹ 5-[4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl]-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  173¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-543-methyl- 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol  174¹ 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(3-fluoro-1H-pyrazol-4- yl)phenol  175¹ 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-pyrazol- 3-yl)phenol  176¹ 5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  177¹ 5-(1-methyl-1H-indazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  178¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (tetrazolo[1,5-b]pyridazin-6-yl)phenol  179¹ 5-[6-(hydroxymethyl)pyrimidin-4-yl]-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol  180¹ 2-[3-(2,9-diazaspiro[5.5]undecan-9-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  181¹ 2-[3-(2,8-diazaspiro[4.5]decan-8-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  182¹ 2-[3-(2-methyl-2,9-diazaspiro[5.5]undecan-9-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol  183¹ 2-[3-(2-methyl-2,8-diazaspiro[5.5]decan-8-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol  184¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[3,4-c]pyridin-5-yl)phenol  185¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(quinolin- 6-yl)phenol  186¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1-methyl- 1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol  187¹ 2-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(1H-imidazol-1- yl)phenol  188¹ 5-(2H-1,3-benzodioxo1-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  189¹ 5-(3-fluoro-1H-pyrazol-4-yl)-2-(3-{[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4- yl]amino}-1,2,4-triazin-6-yl)phenol  190¹ 2-{3-{[(2S)-2-aminopropyl](methyl)amino}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  191¹ 5-(5-fluoro-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-3-yl}phenol 192 5-[1-(²H₃)methyl-1H-pyrazol-4-yl]-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-3-yl}phenol  193¹ 2-{3-[(3aR,4R,6aS)-4-(tert-butylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-1,2,4- triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol  194¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[3,4-b]pyrazin-5-yl)phenol  195¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[4,3-d]pyrimidin-5-yl)phenol  196¹ 5-(1-methyl-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-3-yl}phenol  197¹ 2-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(4-methyl-1H-imidazol- 1-yl)phenol  198¹ 5-(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  199¹ 5-(1-methyl-1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  200¹ 5-(1-methyl-1H-benzotriazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol 201 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1-methyl-1H-pyrazol-4-yl)phenol  202¹ 2-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-pyrazol- 4-yl)phenol  203¹ 5-(1-methyl-1H-pyrazol-4-yl)-2-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  204¹ 2-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(2H-1,2,3-triazol-2- yl)phenol  205¹ 2-{3-[3-(methylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-pyrazol-4- yl)phenol  206¹ 2-{3-[4-(tert-butylamino)piperidin-l-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol  207¹ 2-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-([1,2,3]triazolo[1,5- a]pyridin-5-yl)phenol  208¹ 2-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-indazol- 5-yl)phenol  209¹ 2-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(pyrimidin-2-yl)phenol  210¹ 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-2H-1,2,3- triazol-4-yl)phenol  211¹ 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-2H-tetrazol- 5-yl)phenol  212¹ 2-{3-[3-(tert-butylamino)piperidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol  213¹ 5-(1-methyl-1H-pyrazol-3-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  214¹ 4-(4-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-3-hydroxyphenyl)-1- methylpyridin-2(1H)-one  215¹ 2-{3-[3-(tert-butylamino)pyrrolidin1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol  216¹ 6-(4-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-3-hydroxyphenyl)-3- methylpyrimidin-4(3H)-one  217¹ 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(6-methoxypyrimidin-4- yl)phenol  218¹ 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2H-1,2,3-triazol-2- yl)phenol  219¹ 5-(4-fluoro-1H-pyrazol-1-yl)-2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6- yl}phenol  220¹ 5-(1H-imidazol-1-yl)-2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}phenol  221¹ 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)phenol  222¹ 5-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  223¹ 2-{3-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H- indazol-5-yl)phenol  224¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)phenol 225 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-1,2,3-triazol-4- yl)phenol  226¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H- pyrazol-4-yl)phenol  227¹ 4-[3-hydroxy-4-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)phenyl]- 1-methylpyridin-2(1H)-one  228¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(4-methyl-1H- imidazol-1-yl)phenol  229¹ 5-(4-fluoro-1H-pyrazol-1-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol  230¹ 5-(4-fluoro-1H-imidazol-1-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol  231¹ 5-(1H-imidazol-1-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6- yl]phenol  232¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(2H-1,2,3-triazol- 2-yl)phenol  233¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H- pyrazol-3-yl)phenol  234¹ 6-[3-hydroxy-4-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)phenyl]- 3-methylpyrimidin-4(3H)-one  235¹ 5-(5-fluoro-1H-pyrazol-4-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  236¹ 5-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}- 1,2,4-triazin-6-yl)phenol  237¹ 2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1,2,4-thiadiazol-5- yl)phenol  238¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1H-imidazol-1-yl)phenol  239¹ 2-{3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (4-methyl-1H-imidazol-1-yl)phenol  240¹ 5-(4-fluoro-1H-imidazol-1-yl)-2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4- yl]amino}-1,2,4-triazin-6-yl)phenol  241¹ 4-{3-hydroxy-4-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6- yl]phenyl}-1-methylpyridin-2(1H)-one  242¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(2-methyl-2H- 1,2,3-triazol-4-yl)phenol  243¹ 5-(6-methoxypyrimidin-4-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol  244¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(pyrimidin-2- yl)phenol  245¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-1,2,3-triazol- 4-yl)phenol  246¹ 6-[4-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6- yl)-3-hydroxyphenyl]-3-methylpyrimidin-4(3H)-one  247¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1H-1,2,3-triazol-4-yl)phenol 248 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (imidazo[1,2-a]pyrazin-6-yl)phenol  249¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (imidazo[1,2-b]pyridazin-6-yl)phenol  250¹ 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1,3-oxazol-2-yl)phenol  251¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(2-methyl-2H- tetrazol-5-yl)phenol  252¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1,3-oxazol-2- yl)phenol  253¹ 5-(1-methyl-1H-pyrazol-3-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  254¹ 5-(6-methoxypyrimidin-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol 255 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(2H-1,2,3- triazol-2-yl)phenol  256¹ 5-(imidazo[1,2-b]pyridazin-6-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol  257¹ 5-(imidazo[1,2-a]pyrazin-6-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol  258¹ 2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-1,2,3-triazol-4- yl)phenol  259¹ 5-(2-methyl-2H-tetrazol-5-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  260¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1-methyl-1H-indazol-5-yl)phenol  261¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1-methyl-1H-pyrazol-3-yl)phenol  262¹ 2-[3-(3,5-dimethylpiperazin-1-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  263¹ 2-[3-(3,5-dimethylpiperazin-1-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H-pyrazol-3- yl)phenol  264¹ 2-(3-{3-(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(2H-1,2,3-triazol-2- yl)phenol  265¹ 5-(6-methoxypyrimidin-4-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  266¹ 5-(2-methyl-2H-1,2,3-triazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  267¹ 5-(2-methyl-2H-tetrazol-5-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  268¹ 5-(6-methoxypyrimidin-4-yl)-2-{3-[(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6- yl}phenol  269¹ 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1,2,4-thiadiazol-5- yl)phenol  270¹ 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(pyrimidin-2-yl)phenol  271¹ 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)phenol  272¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1,2,4-thiadiazol-5- yl)phenol  273¹ 5-(1H-imidazol-1-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol  274¹ 5-(4-methyl-1H-imidazol-1-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  275¹ 5-(4-fluoro-1H-imidazol-1-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  276¹ 5-(4-fluoro-1H-pyrazol-1-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  277¹ 5-(2-methyl-1,3-oxazol-5-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]1,2,4- triazin-6-yl}phenol  278¹ 2-{3-[3-(tert-butylamino)-4-fluoropyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol  279¹ 5-(pyrimidin-2-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol 280 5-(7-fluoro-1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol 281 5-(1-methyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  282¹ 5-(1H-pyrazol-4-yl)-2-[3-(3,3,5,5-tetramethylpiperazin-1-yl)-1,2,4-triazin-6-yl]phenol  283¹ 5-(imidazo[1,2-a]pyrazin-6-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  284¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1-methyl-1H-pyrazolo]3,4-b]pyridin-5-yl)phenol  285¹ 5-(1-methyl-1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol 286 2-(3-{[(3S,4S)-3-methoxy-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)- 5-(1H-pyrazol-4-yl)phenol  287¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (2-methyl-2H-1,2,3-triazol-4-yl)phenol  288¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1,3-oxazol-2-yl)phenol  289¹ 5-(2-methyl-1,3-oxazol-5-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-l-yl}-1,2,4- triazin-6-yl)phenol  290¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (6-methoxypyrimidin-4-yl)phenol  291¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (2-methyl-2H-tetrazol-5-yl)phenol  292¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1,2,4-thiadiazol-5-yl)phenol  293¹ 2-(3-{[(3S,4S)-3-methoxy-2,2,6,6-tetramethylpiperidin-4-yl](methyl)amino}-1,2,4- triazin-6-yl)-5-(1H-pyrazol-4-yl)phenol  294¹ 5-(imidazo]1,2-Npyridazin-6-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-l-yl}-1,2,4- triazin-6-yl)phenol  295¹ 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-2H-1,2,3- triazol-4-yl)phenol  296¹ 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-pyrazol-3- yl)phenol  297¹ 2-(3-{3-[(2-methylpropyl)aminolpyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  298¹ (3S,4S)-4-({6-[2-hydroxy-4-(1H-pyrazol-4-yl)phenyl]-1,2,4-triazin-3-yl}amino)- 2,2,6,6-tetramethylpiperidin-3-ol  299¹ 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(2-methyl-1,3- oxazol-5-yl)phenol  300¹ 5-(7-fluoro-1-methyl-1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  301¹ 5-(6,7-difluoro-1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol  302¹ 5-(6,7-difluoro-1-methyl-1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  303¹ 5-(8-methylimidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]-1,2,4-triazin-6-yl}phenol  304¹ 5-(8-methoxyimidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]-1,2,4-triazin-6-yl}phenol  305¹ 2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,2,4-triazin-6- yl)phenol  306¹ 2-{3-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol  307¹ 5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin- 1-yl}-1,2,4-triazin-6-yl)phenol  308¹ 5-(1,3-oxazol-2-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-l-yl}-1,2,4-triazin-6- yl)phenol  309¹ 2-(3-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  310¹ 2-{3-[(4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1,2,4-triazin-6-yl}- 5-(1H-pyrazol-4-yl)phenol  311¹ 2-{3-[(4aS,7aR)-4-methylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-1,2,4-triazin- 6-yl}-5-(1H-pyrazol-4-yl)phenol 312 2-(3-{3-[(oxetan-3-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol 313 5-(1-methyl-1H-pyrazol-4-yl)-2-(3-{3-[(oxetan-3-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  314¹ 5-(pyridazin-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol  315¹ 5-[(pyridin-3-yl)amino]2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin- 6-yl}phenol  316¹ 2-(3-{3-[(1-fluoro-2-methylpropan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol  317¹ 2-{3-[3-(ethylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol  318¹ 2-{3-[3-(dimethylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol  319¹ 5-(1-methyl-1H-indazol-5-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  320¹ 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-2H-tetrazol-5- yl)phenol  321¹ 5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol  322¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol  323¹ 2-(3-{[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol  324¹ 2-{3-[(3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2H- 1,2,3-triazol-2-yl)phenol 325 2-{3-[(3-methyloxetan-3-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol  326¹ 5-(4-methyl-1H-imidazol-1-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  327¹ 2-{3-[(3aR,7aR)-octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol  328¹ 2-[3-(piperazin-1-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  329¹ 2-{3-[(3S)-3-{[(2R)-1-fluoropropan-2-yl]amino}pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5- (1H-pyrazol-4-yl)phenol  330¹ 5-(1-methyl-1H-indazol-5-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  331¹ 5-(1H-imidazol-1-yl)-2-(3-{3-(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6- yl)phenol  332¹ 2-{3-[(3aR,6aS)-hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol  333¹ 2-(3-{3-[(2-hydroxyethyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  334¹ 2-[3-(8-amino-2-oxa-6-azaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol  335¹ 2-(3-{3-[(oxan-4-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  336¹ 2-(3-{3-[(1-methoxypropan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol  337¹ 2-[3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol  338¹ 5-(4-fluoro-1H-pyrazol-1-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol  339¹ 2-[3-(1,7-diazaspiro[4.4]nonan-7-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  340¹ 2-(3-{3-[(1-methylcyclopropyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol  341¹ 2-(3-{3-[(1-methoxy-2-methylpropan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)- 5-(1H-pyrazol-4-yl)phenol 342 5-(1-methyl-1H-indazol-5-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-3-yl}phenol 343 5-(1-methyl-1H-pyrazol-3-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-3-yl}phenol  344¹ 6-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)imidazo[1,2-b]pyridazine-8-carbonitrile  345¹ 2-(3-{[(3R,4S)-3-fluoropiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  346¹ 2-{3-[(3R,4R)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol  347¹ 2-(3-{(3S)-3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  348¹ 2-(3-{(3R)-3-[(propan-2-yl)amino]pyrrolidin-l-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol  349¹ 2-(3-{3-[(bicyclo[1.1.1]pentan-1-yl)amino]pyrrolidin-l-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol  350¹ 2-{3-[3-(methylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-1,3-oxazol-5- yl)phenol  351¹ 5-[8-(aminomethyl)imidazo[1,2-b]pyridazin-6-yl]-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol  352¹ 5-(1,3-oxazol-2-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol  353¹ 2-[3-(6-oxa-2,9-diazaspiro[4.5]decan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol  354¹ 2-[3-(2,7-diazaspirol{4.4}nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  355¹ 2-{3-[(3S)-3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol  356¹ 2-{3-[(3R)-3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol  357¹ 2-{3-[3-(cyclopentylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol  358¹ 2-{3-[3-(methylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(1,3-oxazol-2-yl)phenol  359¹ 5-(imidazo[1,2-a]pyrazin-2-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  360¹ 5-(imidazo[1,2-a]pyridin-2-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol  361¹ 2-[3-(3-{[(propan-2-yl)amino]methyl}pyrrolidin-l-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol  362¹ 2-(3-{3-[(4-methyloxan-4-yl)amino]pyrrolidin-l-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol  363¹ 2-{6-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-3-yl}-5-(1H-pyrazol-4- yl)phenol  364¹ 2-{3-[3-(methylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-[6- (methylsulfanyl)pyrimidin-4-yl]phenol  365¹ 2-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-(3-chloro-1H-pyrazol-4- yl)phenol  366¹ 4-(4-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl]-3-hydroxyphenyl)-1H- pyrazole-3-carbonitrile  367¹ 2-{3-[3-(tert-butylamino)pyrrolidin-l-yl]-1,2,4-triazin-6-yl}-5-[1-(²H₃)methyl-1H- pyrazol-4-yl]phenol  368¹ 3-(1-methyl-1H-pyrazol-3-yl)-6-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}benzene-1,2-diol  369¹ 2-[3-(2,7-diazaspiro[4.5]decan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  370¹ 2-[3-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol  371¹ 2-(3-{3-[(3-hydroxypropyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  372¹ 2-[3-(3-{[(oxan-4-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol- 4-yl)phenol  373¹ 5-[1-(²H₃)methyl-1H-pyrazol-4-yl]-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol  374¹ 2-{6-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-3-yl}-5-(3-fluoro-1H-pyrazol-4- yl)phenol  375¹ 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(3-methyl-1H-pyrazol- 4-yl)phenol  376¹ 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-3-methoxy-5-(1H- pyrazol-4-yl)phenol  377¹ 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- [1-(²H₃)methyl-1H-pyrazol-4-yl]phenol  378¹ 2-{3-[(3S)-3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(3-fluoro-1H- pyrazol-4-yl)phenol  379¹ 2-{3-[(3R)-3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(3-fluoro-1H- pyrazol-4-yl)phenol 380 5-[6-(methylamino)pyrimidin-4-yl]-2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4- triazin-6-yl}phenol  381¹ 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[3,4-c]pyridin-1-yl)phenol 382 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(pyridin- 4-yl)phenol 383 5-(7-fluoro-1H-indazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol 384 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(pyridin- 3-yl)phenol  385¹ 2-{3-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1,2,4-triazin-6-yl}-5-(imidazo[1,2- b]pyridazin-6-yl)phenol  386¹ 2-(3-{3-[(cyclopentylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol  387¹ 2-[3-([2,3’-bipyrrolidin]-l’-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol  388¹ 5-(1H-pyrazol-4-yl)-2-{3-[-({[(pyridin-2-yl)methyl]amino}methyl)pyrrolidin-1-yl]- 1,2,4-triazin-6-yl}phenol 389 2-[3-(3-amino-3-methylpyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H-pyrazol-4- yl)phenol  390¹ 2-(3-{3-[(tert-butylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  391¹ 2-[3-(3-{[(4-methyloxan-4-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol  392¹ 2-(3-{3-[(cyclopropylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol 393 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(pyridin- 2-yl)phenol 394 5-(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-{6-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}phenol  395¹ 2-[3-(3-{[(oxolan-3-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol  396¹ 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3- yl}phenol 397 2-{3-[(3S)-3-{[(oxan-4-yl)amino]methyl}pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol 398 2-{3-[(3R)-3-{[(oxan-4-yl)amino]methyl}pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol  399¹ 2-{3-[(3R)-3-(cyclobutylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol  400¹ 2-{3-[(3S)-3-(cyclobutylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol  401¹ 2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(2H-1,2,3-triazol- 2-yl)phenol 402 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5- (pyrimidin-2-yl)phenol  403¹ 2-[3-(3-{[(3-fluorooxan-4-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol  404¹ 2-[3-(3-{[(oxan-3-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol- 4-yl)phenol  405¹ 2-[3-(3-{[(8-oxabicyclo[3.2.1]octan-3-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin- 6-yl]-5-(1H-pyrazol-4-yl)phenol  406¹ 2-{3-[(3R)-3-(cyclobutylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H- pyrazol-4-yl)phenol  407¹ 2-{3-[(3S)-3-(cyclobutylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H- pyrazol-4-yl)phenol  408¹ 2-(3-[(1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino}-1,2,4- triazin-6-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol  409¹ 2-(3-{3-[(3,3-difluorocyclopentyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol  410¹ 2-(3-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol 411 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5- (pyrimidin-4-yl)phenol 412 2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(pyrazin- 2-yl)phenol  413¹ 2-(3-{3-[(methylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol  414¹ 2-[3-(3-{1-[(propan-2-yl)amino]ethyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol  415¹ 2-(3-{3-[(cyclobutylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol  416¹ 2-(3-{3-[(cyclobutylamino)methyl}pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1-methyl-1H- pyrazol-4-yl)phenol  417¹ 2-(3-{[1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl}(methyl)amino}-1,2,4- triazin-6-yl)-5-(2H-1,2,3-triazol-2-yl)phenol  418¹ 6-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-2-fluoro-3-(1H-pyrazol-4- yl)phenol  419¹ 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4-triazin-3- yl}phenol  420¹ 2-(3-{3-[(3-fluorocyclopentyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol  421¹ 2-[3-(3-{1-[(oxan-4-yl)amino]cyclopropyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol  422¹ 2-(3-{3-methyl-3-[(propan-2-yl)aminolpyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1- methyl-1H-pyrazol-4-yl)phenol  423¹ 2-{6-[(3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(1H- pyrazol-4-yl)phenol,and  424¹ 5-[1-(²H₃)methyl-1H-pyrazol-4-yl]-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-3-yl}phenol; 425 2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)-5-(5-methyl- 1H-pyrazol-4-yl)phenol

-   -   wherein a form of the compound is selected from the group         consisting of a salt, hydrate, solvate, racemate, enantiomer,         diastereomer, stereoisomer, and tautomer form thereof.

Another aspect of the compound of Formula (I) or Formula (II) or a form thereof is a compound salt selected from the group consisting of:

Cpd Name 1 5-(5-methyl-1,3-oxazol-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrobromide 2 5-(6-methoxypyrimidin-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol formate 3 5-(2-methoxypyridin-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol formate 6 5-(3-methyl-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol formate 10 5-(4-methyl-1H-imidazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 11 5-(1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4-triazin-6- yl}phenol dihydrochloride 12 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol ditrifluoroacetate 13 5-(1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol dihydrochloride 14 5-[1-(²H₃)methyl-1H-pyrazol-4-yl]-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol dihydrochloride 15 6-[2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,2,4-triazin-3-amine hydrochloride 16 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol hydrochloride 18 5-(1-methyl-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol dihydrochloride 19 5-(3-fluoro-1-methyl-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol hydrochloride 20 2-{3-[methyl(piperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 23 2-{3-[methyl(piperidin-3-yl)amino]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 24 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2-methyl- 2H-1,2,3-triazol-4-yl)phenol hydrochloride 50 5-(4-fluoro-1H-imidazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol dihydrochloride 51 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(3-methyl- 1H-1,2,4-triazol-1-yl)phenol hydrochloride 52 2-{3-[(1-methylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride 55 5-(4-methoxy-1H-pyrazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol dihydrochloride 57 5-(3-chloro-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 58 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,3- thiazol-2-yl)phenol hydrochloride 59 5-(4-chloro-1H-imidazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol dihydrochloride 60 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (pyridazin-4-yl)phenol dihydrochloride 61 5-(6-methylpyridazin-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol dihydrochloride 62 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1-methyl- 1H-1,2,4-triazol-3-yl)phenol dihydrochloride 63 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2H-1,2,3- triazol-2-yl)phenol dihydrochloride 65 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,2,4- thiadiazol-5-yl)phenol hydrochloride 66 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(3-methyl- 1,2,4-thiadiazol-5-yl)phenol hydrochloride 67 2-{3-[(3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)(methyl)amino]-1,2,4-triazin-6-yl}-5- (1H-pyrazol-4-yl)phenol dihydrochloride 68 1-[1-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin- 6-yl}phenyl)-1H-pyrazol-4-yl]ethan-1-one dihydrochloride 69 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(4-methyl- 2H-1,2,3-triazol-2-yl)phenol dihydrochloride 71 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(pyridin- 2-yl)phenol formate 72 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4- triazin-6-yl}phenol dihydrochloride 73 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol trihydrochloride 74 5-(2-methyl-1,3-oxazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 75 5-(1-methyl-1H-imidazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 76 5-(1-methyl-1H-pyrazol-3-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 77 2-(3-{[(1R,3s,5S)-9-methyl-9-azabicyclo[3.3.1]nonan-3-yl)amino}-1,2,4-triazin-6-yl)- 5-(1H-pyrazol-4-yl)phenol dihydrochloride 79 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H-1,2,4- triazol-1-yl)phenol dihydrochloride 80 5-(imidazo[1,2-a]pyrazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 81 5-(5-methyl-1,3,4-oxadiazol-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol hydrochloride 82 2-{3-[(2,6-dimethylpiperidin-4-yl)oxy]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 84 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (pyridazin-3-yl)phenol formate 86 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (pyrimidin-5-yl)phenol formate 88 5-(4-methoxy-1,3,5-triazin-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol dihydrochloride 89 5-(1H-imidazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol dihydrochloride 90 1-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)-1H-pyrazol-4-ol dihydrochloride 91 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,3- oxazol-5-yl)phenol hydrochloride 92 5-(imidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol hydrochloride 93 5-(4-fluoro-1H-pyrazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol dihydrochloride 94 5-(4-methyl-1H-pyrazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol dihydrochloride 95 2-[3-(2,7-diazaspiro[3.5]nonan-7-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 96 2-[3-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 97 5-(1H-indazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol dihydrochloride 99 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(4-nitro- 2H-1,2,3-triazol-2-yl)phenol dihydrochloride 101 5-(1-cyclopropyl-1H-pyrazol-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol hydrochloride 102 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (pyrimidin-4-yl)phenol formate 103 4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}[1,1′- biphenyl]-3,4′-diol formate 105 6-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}quinolin-7-ol hydrobromide 107 5-(1H-pyrazol-3-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4-triazin-6- yl}phenol ditrifluoroacetate 108 5-(1-methyl-1H-pyrazol-3-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4- triazin-6-yl}phenol trifluoroacetate 109 2-[3-(2,6-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 110 2-[3-(2,6-diazaspiro[3.4]octan-6-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 111 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-3-yl)phenol trifluoroacetate 112 5-(5-fluoropyrimidin-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 113 2-[3-(1-methyl-1,7-diazaspiro[3.5]nonan-7-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol dihydrochloride 114 2-{3-[(3S)-3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol dihydrochloride 115 2-{3-[(7S)-7-amino-5-azaspiro[2.4]heptan-5-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol dihydrochloride 116 2-{3-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol dihydrochloride 117 2-{3-[(3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl]-1,2,4-triazin-6-yl}- 5-(1H-pyrazol-4-yl)phenol dihydrochloride 118 2-[3-(2,6-diazaspiro[3.3]heptan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 119 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(5-methyl- 2H-tetrazol-2-yl)phenol dihydrochloride 120 2-(3-{[(2R,4s,6S)-2,6-diethylpiperidin-4-yl]oxy}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol trifluoroacetate 121 2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2H-1,2,3-triazol- 2-yl)phenol dihydrochloride 122 2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4-triazin-6-yl}-5-(2H-1,2,3-triazol-2- yl)phenol hydrochloride 123 5-(6-chloropyridazin-3-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 124 5-(1-methyl-1H-pyrazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol dihydrochloride 126 2-{3-[(3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol dihydrochloride 127 2-{3-[6-(diethylamino)-3-azabicyclo[3.1.0]hexan-3-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol hydrochloride 128 5-(5-methylpyrimidin-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 129 5-(4-methylpyrimidin-2-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 130 5-(2-chloropyrimidin-4-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 132 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[3,4-b]pyridin-5-yl)phenol formate 133 5-(3-chloro-1H-1,2,4-triazol-1-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol dihydrochloride 134 6-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)pyridazin-3-ol hydrochloride 140 1-[1-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin- 6-yl}phenyl)-1H-imidazol-4-yl]ethan-1-one dihydrochloride 141 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol dihydrochloride 142 5-(2-methylimidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]-1,2,4-triazin-6-yl}phenol dihydrochloride 143 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2-methyl- 2H-tetrazol-5-yl)phenol dihydrochloride 146 6-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)-3-methylpyrimidin-4(3H)-one dihydrochloride 147 5-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)-2-methylpyridazin-3(2H)-one dihydrochloride 148 2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol hydrochloride 151 2-[3-(2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(3-fluoro-1H-pyrazol-4- yl)phenol dihydrochloride 152 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- ([1,2,3]triazolo[1,5-a]pyridin-5-yl)phenol dihydrochloride 153 5-(3-fluoro-1H-pyrazol-4-yl)-2-{3-[(3aS,7aR)-1-methyloctahydro-5H-pyrrolo[3,2- c]pyridin-5-yl]-1,2,4-triazin-6-yl}phenol dihydrochloride 155 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (tetrazolo[1,5-a]pyridin-7-yl)phenol dihydrochloride 156 5-(4-fluoro-1H-pyrazol-3-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol trifluoroacetate 157 2-(3-{3-[(adamantan-1-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol ditrifluoroacetate 158 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(5H- pyrrolo[2,3-b]pyrazin-2-yl)phenol formate 159 2-(3-{3-[(adamantan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol ditrifluoroacetate 160 2-(3-{3-[(3,5-dimethyladamantan-1-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol ditrifluoroacetate 161 5-[4-(hydroxymethyl)-1H-pyrazol-1-yl]-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol hydrochloride 162 2-{3-[(3aR,4R,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-1,2,4- triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 164 5-(1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol hydrochloride 165 2-{3-[(3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl]-1,2,4-triazin-6- yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 166 2-[3-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol dihydrochloride 167 2-{3-[(3aR,4S,6aS)-4-(dimethylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-1,2,4- triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 168 3-amino-6-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenyl)-4-methylpyridin-2-ol dihydrochloride 169 5-(2,7-dimethyl[1,3]oxazolo[5,4-b]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol diformate 172 5-[4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl]-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol hydrochloride 173 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(3-methyl- 3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol hydrochloride 174 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(3-fluoro-1H-pyrazol-4- yl)phenol hydrochloride 175 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-pyrazol- 3-yl)phenol trifluoroacetate 176 5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol formate 177 5-(1-methyl-1H-indazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol formate 178 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5- (tetrazolo[1,5-b]pyridazin-6-yl)phenol dihydrochloride 179 5-[6-(hydroxymethyl)pyrimidin-4-yl]-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol hydrochloride 180 2-[3-(2,9-diazaspiro[5.5]undecan-9-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 181 2-[3-(2,8-diazaspiro[4.5]decan-8-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 182 2-[3-(2-methyl-2,9-diazaspiro[5.5]undecan-9-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol dihydrochloride 183 2-[3-(2-methyl-2,8-diazaspiro[4.5]decan-8-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol dihydrochloride 184 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[3,4-c]pyridin-5-yl)phenol formate 185 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(quinolin- 6-yl)phenol trifluoroacetate 186 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1-methyl- 1H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol hydrochloride 187 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-imidazol-1- yl)phenol ditrifluoroacetate 188 5-(2H-1,3-benzodioxol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol dihydrochloride 189 5-(3-fluoro-1H-pyrazol-4-yl)-2-(3-{[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4- yl]amino}-1,2,4-triazin-6-yl)phenol dihydrochloride 190 2-(3-{[(2S)-2-aminopropyl](methyl)amino}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol dihydrochloride 191 5-(5-fluoro-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-3-yl}phenol hydrochloride 193 2-{3-[(3aR,4R,6aS)-4-(tert-butylamino)hexahydrocyclopenta[c]pyrrol-2(1H)-yl]-1,2,4- triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 194 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[3,4-b]pyrazin-5-yl)phenol formate 195 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[4,3-d]pyrimidin-5-yl)phenol formate 196 5-(1-methyl-1H-pyrazol-4-yl)-2-{6-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-3-yl}phenol hydrochloride 197 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(4-methyl-1H-imidazol- 1-yl)phenol ditrifluoroacetate 198 5-(1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol formate 199 5-(1-methyl-1H-pyrazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol hydrochloride 200 5-(1-methyl-1H-benzotriazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol hydrochloride 202 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-pyrazol- 4-yl)phenol hydrochloride 203 5-(1-methyl-1H-pyrazol-4-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 204 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2H-1,2,3-triazol-2- yl)phenol hydrochloride 205 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-pyrazol-4- yl)phenol hydrochloride 206 2-{3-[4-(tert-butylamino)piperidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol trifluoroacetate 207 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-([1,2,3]triazolo[1,5- a]pyridin-5-yl)phenol dihydrochloride 208 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-indazol- 5-yl)phenol dihydrochloride 209 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(pyrimidin-2-yl)phenol dihydrochloride 210 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-2H-1,2,3- triazol-4-yl)phenol dihydrochloride 211 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-2H-tetrazol- 5-yl)phenol dihydrochloride 212 2-{3-[3-(tert-butylamino)piperidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol trifluoroacetate 213 5-(1-methyl-1H-pyrazol-3-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 214 4-(4-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-3-hydroxyphenyl)-1- methylpyridin-2(1H)-one hydrochloride 215 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H- [1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol hydrochloride 216 6-(4-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-3-hydroxyphenyl)-3- methylpyrimidin-4(3H)-one hydrochloride 217 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(6-methoxypyrimidin-4- yl)phenol ditrifluoroacetate 218 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2H-1,2,3-triazol-2- yl)phenol trihydrochloride 219 5-(4-fluoro-1H-pyrazol-1-yl)-2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6- yl}phenol trihydrochloride 220 5-(1H-imidazol-1-yl)-2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}phenol trihydrochloride 221 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)phenol dihydrochloride 222 5-(1-methyl-1H-pyrazolo[3,4-c]pyridin-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol dihydrochloride 223 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H- indazol-5-yl)phenol trifluoroacetate 224 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)phenol trifluoroacetate 226 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H- pyrazol-4-yl)phenol trifluoroacetate 227 4-[3-hydroxy-4-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)phenyl]- 1-methylpyridin-2(1H)-one hydrochloride 228 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(4-methyl-1H- imidazol-1-yl)phenol hydrochloride 229 5-(4-fluoro-1H-pyrazol-1-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol hydrochloride 230 5-(4-fluoro-1H-imidazol-1-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol hydrochloride 231 5-(1H-imidazol-1-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6- yl]phenol hydrochloride 232 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(2H-1,2,3-triazol- 2-yl)phenol hydrochloride 233 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H- pyrazol-3-yl)phenol hydrochloride 234 6-[3-hydroxy-4-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)phenyl]- 3-methylpyrimidin-4(3H)-one hydrochloride 235 5-(5-fluoro-1H-pyrazol-4-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 236 5-(2-methyl-2H-1,2,3-triazol-4-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}- 1,2,4-triazin-6-yl)phenol hydrochloride 237 2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1,2,4-thiadiazol-5- yl)phenol hydrochloride 238 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1H-imidazol-1-yl)phenol dihydrochloride 239 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (4-methyl-1H-imidazol-1-yl)phenol dihydrochloride 240 5-(4-fluoro-1H-imidazol-1-yl)-2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4- yl]amino}-1,2,4-triazin-6-yl)phenol dihydrochloride 241 4-{3-hydroxy-4-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6- yl]phenyl}-1-methylpyridin-2(1H)-one hydrochloride 242 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(2-methyl-2H- 1,2,3-triazol-4-yl)phenol trifluoroacetate 243 5-(6-methoxypyrimidin-4-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol ditrifluoroacetate 244 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(pyrimidin-2- yl)phenol trifluoroacetate 245 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-1,2,3-triazol- 4-yl)phenol trifluoroacetate 246 6-[4-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6- yl)-3-hydroxyphenyl]-3-methylpyrimidin-4(3H)-one dihydrochloride 247 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1H-1,2,3-triazol-4-yl)phenol dihydrochloride 249 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (imidazo[1,2-b]pyridazin-6-yl)phenol dihydrochloride 250 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1,3-oxazol-2-yl)phenol hydrochloride 251 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(2-methyl-2H- tetrazol-5-yl)phenol trifluoroacetate 252 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1,3-oxazol-2- yl)phenol trifluoroacetate 253 5-(1-methyl-1H-pyrazol-3-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol formate 254 5-(6-methoxypyrimidin-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol formate 256 5-(imidazo[1,2-b]pyridazin-6-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol trifluoroacetate 257 5-(imidazo[1,2-a]pyrazin-6-yl)-2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4- triazin-6-yl]phenol hydrochloride 258 2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-1,2,3-triazol-4- yl)phenol ditrifluoroacetate 259 5-(2-methyl-2H-tetrazol-5-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol trifluoroacetate 260 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1-methyl-1H-indazol-5-yl)phenol dihydrochloride 261 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1-methyl-1H-pyrazol-3-yl)phenol dihydrochloride 262 2-[3-(3,5-dimethylpiperazin-1-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 263 2-[3-(3,5-dimethylpiperazin-1-yl)-1,2,4-triazin-6-yl]-5-(1-methyl-1H-pyrazol-3- yl)phenol hydrochloride 264 2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(2H-1,2,3-triazol-2- yl)phenol hydrochloride 265 5-(6-methoxypyrimidin-4-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 266 5-(2-methyl-2H-1,2,3-triazol-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol dihydrochloride 267 5-(2-methyl-2H-tetrazol-5-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol dihydrochloride 268 5-(6-methoxypyrimidin-4-yl)-2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6- yl}phenol ditrifluoroacetate 269 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1,2,4-thiadiazol-5- yl)phenol dihydrochloride 270 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(pyrimidin-2-yl)phenol dihydrochloride 271 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)phenol dihydrochloride 272 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1,2,4-thiadiazol-5- yl)phenol trifluoroacetate 273 5-(1H-imidazol-1-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol hydrochloride 274 5-(4-methyl-1H-imidazol-1-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol hydrochloride 275 5-(4-fluoro-1H-imidazol-1-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol hydrochloride 276 5-(4-fluoro-1H-pyrazol-1-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol hydrochloride 277 5-(2-methyl-1,3-oxazol-5-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol hydrochloride 278 2-{3-[3-(tert-butylamino)-4-fluoropyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol hydrochloride 279 5-(pyrimidin-2-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol formate 282 5-(1H-pyrazol-4-yl)-2-[3-(3,3,5,5-tetramethylpiperazin-1-yl)-1,2,4-triazin-6-yl]phenol dihydrochloride 283 5-(imidazo[1,2-a]pyrazin-6-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 284 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)phenol dihydrochloride 285 5-(1-methyl-1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol formate 287 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (2-methyl-2H-1,2,3-triazol-4-yl)phenol trifluoroacetate 288 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1,3-oxazol-2-yl)phenol trifluoroacetate 289 5-(2-methyl-1,3-oxazol-5-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 290 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (6-methoxypyrimidin-4-yl)phenol trifluoroacetate 291 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (2-methyl-2H-tetrazol-5-yl)phenol trifluoroacetate 292 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1,2,4-thiadiazol-5-yl)phenol trifluoroacetate 293 2-(3-{[(3S,4S)-3-methoxy-2,2,6,6-tetramethylpiperidin-4-yl](methyl)amino}-1,2,4- triazin-6-yl)-5-(1H-pyrazol-4-yl)phenol dihydrochloride 294 5-(imidazo[1,2-b]pyridazin-6-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 295 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-2H-1,2,3- triazol-4-yl)phenol dihydrochloride 296 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H-pyrazol-3- yl)phenol dihydrochloride 297 2-(3-{3-[(2-methylpropyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol dihydrochloride 298 (3S,4S)-4-({6-[2-hydroxy-4-(1H-pyrazol-4-yl)phenyl]-1,2,4-triazin-3-yl}amino)- 2,2,6,6-tetramethylpiperidin-3-ol dihydrochloride 299 2-[3-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(2-methyl-1,3- oxazol-5-yl)phenol trifluoroacetate 300 5-(7-fluoro-1-methyl-1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol formate 301 5-(6,7-difluoro-1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol formate 302 5-(6,7-difluoro-1-methyl-1H-benzimidazol-5-yl)-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol formate 303 5-(8-methylimidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]-1,2,4-triazin-6-yl}phenol formate 304 5-(8-methoxyimidazo[1,2-b]pyridazin-6-yl)-2-{3-[methyl(2,2,6,6-tetramethylpiperidin- 4-yl)amino]-1,2,4-triazin-6-yl}phenol formate 305 2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1,2,4-triazin-6- yl)phenol trifluoroacetate 306 2-{3-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol dihydrochloride 307 5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin- 1-yl}-1,2,4-triazin-6-yl)phenol hydrochloride 308 5-(1,3-oxazol-2-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6- yl)phenol hydrochloride 309 2-(3-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol hydrochloride 310 2-{3-[(4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1,2,4-triazin-6-yl}- 5-(1H-pyrazol-4-yl)phenol trihydrochloride 311 2-{3-[(4aS,7aR)-4-methylhexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-1,2,4-triazin- 6-yl}-5-(1H-pyrazol-4-yl)phenol trihydrochloride 314 5-(pyridazin-4-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol formate 315 5-[(pyridin-3-yl)amino]-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin- 6-yl}phenol formate 316 2-(3-{3-[(1-fluoro-2-methylpropan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol hydrochloride 317 2-{3-[3-(ethylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydrochloride 318 2-{3-[3-(dimethylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4-yl)phenol dihydroiodide 319 5-(1-methyl-1H-indazol-5-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol trihydrochloride 320 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-2H-tetrazol-5- yl)phenol trihydrochloride 321 5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4- yl)amino]-1,2,4-triazin-6-yl}phenol trihydrochloride 322 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol dihydrochloride 323 2-(3-{[(3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- (1H-pyrazol-4-yl)phenol dihydrochloride 324 2-{3-[(3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(2H- 1,2,3-triazol-2-yl)phenol dihydrochloride 326 5-(4-methyl-1H-imidazol-1-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 327 2-{3-[(3aR,7aR)-octahydro-2H-pyrrolo[3,4-c]pyridin-2-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol trihydrochloride 328 2-[3-(piperazin-1-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 329 2-{3-[(3S)-3-{[(2R)-1-fluoropropan-2-yl]amino}pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5- (1H-pyrazol-4-yl)phenol dihydrochloride 330 5-(1-methyl-1H-indazol-5-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 331 5-(1H-imidazol-1-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6- yl)phenol hydrochloride 332 2-{3-[(3aR,6aS)-hexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol dihydrochloride 333 2-(3-{3-[(2-hydroxyethyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol dihydrochloride 335 2-(3-{3-[(oxan-4-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol dihydrochloride 336 2-(3-{3-[(1-methoxypropan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol dihydrochloride 337 2-[3-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol dihydrochloride 338 5-(4-fluoro-1H-pyrazol-1-yl)-2-(3-{3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4- triazin-6-yl)phenol hydrochloride 339 2-[3-(1,7-diazaspiro[4.4]nonan-7-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 340 2-(3-{3-[(1-methylcyclopropyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol dihydrochloride 341 2-(3-{3-[(1-methoxy-2-methylpropan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)- 5-(1H-pyrazol-4-yl)phenol dihydrochloride 344 6-(3-hydroxy-4-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenyl)imidazo[1,2-b]pyridazine-8-carbonitrile formate 345 2-(3-{[(3R,4S)-3-fluoropiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol dihydrochloride 346 2-{3-[(3R,4R)-3-methoxy-4-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H- pyrazol-4-yl)phenol dihydrochloride 347 2-(3-{(3S)-3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol trifluoroacetate 348 2-(3-{(3R)-3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol trifluoroacetate 349 2-[3-{3-[(bicyclo[1.1.1]pentan-1-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol trifluoroacetate 350 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(2-methyl-1,3-oxazol-5- yl)phenol dihydrochloride 351 5-[8-(aminomethyl)imidazo[1,2-b]pyridazin-6-yl]-2-{3-[methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}phenol formate 352 5-(1,3-oxazol-2-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6- yl}phenol formate 353 2-[3-(6-oxa-2,9-diazaspiro[4.5]decan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol dihydrochloride 354 2-[3-(2,7-diazaspiro[4.4]nonan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 355 2-{3-[(3S)-3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol dihydrochloride 356 2-{3-[(3R)-3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol dihydrochloride 357 2-{3-[3-(cyclopentylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol dihydrochloride 358 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1,3-oxazol-2-yl)phenol dihydrochloride 359 5-(imidazo[1,2-a]pyrazin-2-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol hydrochloride 360 5-(imidazo[1,2-a]pyridin-2-yl)-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4- triazin-6-yl}phenol hydrochloride 361 2-[3-(3-{[(propan-2-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol dihydrochloride 362 2-(3-{3-[(4-methyloxan-4-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol ditrifluoroacetate 363 2-{6-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-3-yl}-5-(1H-pyrazol-4- yl)phenol dihydrochloride 364 2-{3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-[6- (methylsulfanyl)pyrimidin-4-yl]phenol trihydrochloride 365 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(3-chloro-1H-pyrazol-4- yl)phenol dihydrochloride 366 4-(4-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-3-hydroxyphenyl)-1H- pyrazole-3-carbonitrile dihydrochloride 367 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-[1-(²H₃)methyl-1H- pyrazol-4-yl]phenol hydrochloride 368 3-(1-methyl-1H-pyrazol-3-yl)-6-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}benzene-1,2-diol trifluoroacetate 369 2-[3-(2,7-diazaspiro[4.5]decan-2-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 370 2-[3-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4- yl)phenol dihydrochloride 371 2-(3-{3-[(3-hydroxypropyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol dihydrochloride 372 2-[3-(3-{[(oxan-4-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol- 4-yl)phenol ditrifluoroacetate 373 5-[1-(²H₃)methyl-1H-pyrazol-4-yl]-2-{3-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-6-yl}phenol hydrochloride 374 2-{6-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-3-yl}-5-(3-fluoro-1H-pyrazol-4- yl)phenol dihydrochloride 375 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(3-methyl-1H-pyrazol- 4-yl)phenol dihydrochloride 376 2-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-3-methoxy-5-(1H- pyrazol-4-yl)phenol trifluoroacetate 377 2-(3-{[(3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl]amino}-1,2,4-triazin-6-yl)-5- [1-(²H₃)methyl-1H-pyrazol-4-yl]phenol hydrochloride 378 2-{3-[(3S)-3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(3-fluoro-1H- pyrazol-4-yl)phenol dihydrochloride 379 2-{3-[(3R)-3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(3-fluoro-1H- pyrazol-4-yl)phenol dihydrochloride 381 2-{3-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-yl}-5-(1H- pyrazolo[3,4-c]pyridin-1-yl)phenol formate 385 2-{3-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1,2,4-triazin-6-yl}-5-(imidazo[1,2- b]pyridazin-6-yl)phenol trifluoroacetate 386 2-(3-{3-[(cyclopentylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol dihydrochloride 387 2-[3-([2,3′-bipyrrolidin]-1′-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol dihydrochloride 388 5-(1H-pyrazol-4-yl)-2-{3-[3-({[(pyridin-2-yl)methyl]amino}methyl)pyrrolidin-1-yl]- 1,2,4-triazin-6-yl}phenol ditrifluoroacetate 390 2-(3-{3-[(tert-butylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol dihydrochloride 391 2-[3-(3-{[(4-methyloxan-4-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol trifluoroacetate 392 2-(3-{3-[(cyclopropylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol formate 395 2-[3-(3-{[(oxolan-3-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol hydrochloride 396 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3- yl}phenol hydrochloride 399 2-{3-[(3R)-3-(cyclobutylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol dihydrochloride 400 2-{3-[(3S)-3-(cyclobutylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1H-pyrazol-4- yl)phenol dihydrochloride 401 2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(2H-1,2,3-triazol- 2-yl)phenol hydrochloride 403 2-[3-(3-{[(3-fluorooxan-4-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol hydrochloride 404 2-[3-(3-{[(oxan-3-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H-pyrazol- 4-yl)phenol hydrochloride 405 2-[3-(3-{[(8-oxabicyclo[3.2.1]octan-3-yl)amino]methyl}pyrrolidin-1-yl)-1,2,4-triazin- 6-yl]-5-(1H-pyrazol-4-yl)phenol hydrochloride 406 2-{3-[(3R)-3-(cyclobutylamino)pyrrolidin-1-yl]-l,2,4-triazin-6-yl}-5-(1-methyl-1H- pyrazol-4-yl)phenol hydrochloride 407 2-{3-[(3S)-3-(cyclobutylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-5-(1-methyl-1H- pyrazol-4-yl)phenol hydrochloride 408 2-(3-{[(1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino}-1,2,4- triazin-6-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol trifluoroacetate 409 2-(3-{3-[(3,3-difluorocyclopentyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol dihydrochloride 410 2-(3-{3-[(dimethylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol dihydrochloride 413 2-(3-{3-[(methylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol-4- yl)phenol dihydrochloride 414 2-[3-(3-{1-[(propan-2-yl)amino]ethyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol dihydrochloride 415 2-(3-{3-[(cyclobutylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H-pyrazol- 4-yl)phenol dihydrochloride 416 2-(3-{3-[(cyclobutylamino)methyl]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1-methyl-1H- pyrazol-4-yl)phenol hydrochloride 417 2-(3-{[(1R,3s,5S)-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl](methyl)amino}-1,2,4- triazin-6-yl)-5-(2H-1,2,3-triazol-2-yl)phenol trifluoroacetate 418 6-{3-[3-(tert-butylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl}-2-fluoro-3-(1H-pyrazol-4- yl)phenol dihydrochloride 419 5-(1H-pyrazol-4-yl)-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,2,4-triazin-3- yl}phenol hydrochloride 420 2-(3-{3-[(3-fluorocyclopentyl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1H- pyrazol-4-yl)phenol dihydrochloride 421 2-[3-(3-{1-[(oxan-4-yl)amino]cyclopropyl}pyrrolidin-1-yl)-1,2,4-triazin-6-yl]-5-(1H- pyrazol-4-yl)phenol dihydrochloride 422 2-(3-{3-methyl-3-[(propan-2-yl)amino]pyrrolidin-1-yl}-1,2,4-triazin-6-yl)-5-(1- methyl-1H-pyrazol-4-yl)phenol trifluoroacetate 423 2-{6-[(3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-3-yl}-5-(1H- pyrazol-4-yl)phenol hydrochloride, and 424 5-[1-(²H₃)methyl-1H-pyrazol-4-yl]-2-{6-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]- 1,2,4-triazin-3-yl}phenol hydrochloride;

-   -   wherein a form of the compound is selected from the group         consisting of a salt, hydrate, solvate, racemate, enantiomer,         diastereomer, stereoisomer, and tautomer form thereof.

An aspect of the present description includes a method for preventing, treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a method for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.

Another aspect of the present description includes a method for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound salt of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a method for use of a compound of Formula (I) or Formula (II) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form or composition thereof.

Another aspect of the present description includes a method for use of a compound salt of Formula (I) or Formula (II) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof.

Another aspect of the present description includes a use for a compound salt of Formula (I) or Formula (II) or a form thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

Another aspect of the present description includes a use for a compound salt of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof in combination with an effective amount of the one or more agents.

Another aspect of the present description includes a use for a compound salt of Formula (I) or Formula (II) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or Formula (II) or a form thereof in combination with an effective amount of the one or more agents.

Chemical Definitions

The chemical terms used above and throughout the description herein, unless specifically defined otherwise, shall be understood by one of ordinary skill in the art to have the following indicated meanings.

As used herein, the term “C₁₋₄alkyl” generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a straight or branched chain configuration, including, but not limited to, methyl, ethyl, n-propyl (also referred to as propyl or propanyl), isopropyl, n-butyl (also referred to as butyl or butanyl), isobutyl, sec-butyl, tert-butyl and the like. A C₁₋₄alkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term “C₂₋₄alkenyl” generally refers to partially unsaturated hydrocarbon radicals having from two to four carbon atoms in a straight or branched chain configuration and one or more carbon-carbon double bonds therein, including, but not limited to, ethenyl (also referred to as vinyl), allyl, propenyl and the like. A C₂₋₄alkenyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term “C₂₋₈alkynyl” generally refers to partially unsaturated hydrocarbon radicals having from two to eight carbon atoms in a straight or branched chain configuration and one or more carbon-carbon triple bonds therein, including, but not limited to, ethynyl, propynyl, butynyl and the like. In certain aspects, C₂₋₈alkynyl includes, but is not limited to, C₂₋₆alkynyl, C₂₋₄alkynyl and the like. A C₂₋₈alkynyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term “C₁₋₄alkoxy” generally refers to saturated hydrocarbon radicals having from one to four carbon atoms in a straight or branched chain configuration of the formula: —O—C₁₋₄alkyl, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. A C₁₋₄alkoxy radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term “C₃₋₁₀cycloalkyl” generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon radical, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and the like. A C₃₋₁₀cycloalkyl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term “aryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical, including, but not limited to, phenyl, naphthyl, anthracenyl, fluorenyl, azulenyl, phenanthrenyl and the like. An aryl radical is optionally substituted with substituent species as described herein where allowed by available valences.

As used herein, the term “heteroaryl” generally refers to a monocyclic, bicyclic or polycyclic aromatic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with one or more heteroatoms, such as an O, S or N atom, including, but not limited to, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, 1,3-thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indazolyl, indolizinyl, isoindolyl, benzofuranyl, benzothienyl, benzoimidazolyl, 1,3-benzothiazolyl, 1,3-benzoxazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, 1,3-diazinyl, 1,2-diazinyl, 1,2-diazolyl, 1,4-diazanaphthalenyl, acridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 6H-thieno[2,3-b]pyrrolyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl and the like. A heteroaryl radical is optionally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by available valences.

In certain aspects, the nomenclature for a heteroaryl radical may differ, such as in non-limiting examples where furanyl may also be referred to as furyl, thienyl may also be referred to as thiophenyl, pyridinyl may also be referred to as pyridyl, benzothienyl may also be referred to as benzothiophenyl and 1,3-benzoxazolyl may also be referred to as 1,3-benzooxazolyl.

In certain other aspects, the term for a heteroaryl radical may also include other regioisomers, such as in non-limiting examples where the term pyrrolyl may also include 2H-pyrrolyl, 3H-pyrrolyl and the like, the term pyrazolyl may also include 1H-pyrazolyl and the like, the term imidazolyl may also include 1H-imidazolyl and the like, the term triazolyl may also include 1H-1,2,3-triazolyl and the like, the term oxadiazolyl may also include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and the like, the term tetrazolyl may also include 1H-tetrazolyl, 2H-tetrazolyl and the like, the term indolyl may also include 1H-indolyl and the like, the term indazolyl may also include 1H-indazolyl, 2H-indazolyl and the like, the term benzoimidazolyl may also include 1H-benzoimidazolyl and the term purinyl may also include 9H-purinyl and the like.

As used herein, the term “heterocyclyl” generally refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic carbon atom ring structure radical in which one or more carbon atom ring members have been replaced, where allowed by structural stability, with a heteroatom, such as an O, S or N atom, including, but not limited to, oxiranyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, triazolinyl, triazolidinyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolinyl, thiadiazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydro-2H-pyranyl, thiopyranyl, 1,3-dioxanyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,4-diazepanyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, 2,3-dihydro-1,4-benzodioxinyl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, octahydro-2H-pyrido[1,2-a]pyrazinyl, 3-azabicyclo[3.1.0]hexyl, (1R,5S)-3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, (1R,5S)-8-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]oct-2-enyl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-enyl, 9-azabicyclo[3.3.1]nonyl, (1R,5S)-9-azabicyclo[3.3.1]nonyl, 2,5-diazabicyclo[2.2.1]heptyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octyl, 1,4-diazabicyclo[3.2.2]nonyl, azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2,7-diazaspiro[3.5]nonyl, 5,8-diazaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 6,9-diazaspiro[4.5]decyl, 7-azadispiro[5.1.5⁸.3⁶]hexadecanyl and the like. A heterocyclyl radical is optionally substituted on a carbon or nitrogen atom ring member with substituent species as described herein where allowed by available valences.

In certain aspects, the nomenclature for a heterocyclyl radical may differ, such as in non-limiting examples where 1,3-benzodioxolyl may also be referred to as benzo[d][1,3]dioxolyl and 2,3-dihydro-1,4-benzodioxinyl may also be referred to as 2,3-dihydrobenzo[b][1,4]dioxinyl.

As used herein, the term “C₁₋₄alkoxy-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-O—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkoxy-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-O—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkoxy-C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl-O—C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkoxy-C₁₋₄alkyl-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-NH—C₁₋₄alkyl-O—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkoxy-C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-N(C₁₋₄alkyl-O—C₁₋₄alkyl)₂.

As used herein, the term “(C₁₋₄alkoxy-C₁₋₄alkyl)(C₁₋₄alkyl)amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl-O—C₁₋₄alkyl).

As used herein, the term “C₁₋₄alkoxy-C₁₋₄alkyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH—C₁₋₄alkyl-O—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkoxy-C₁₋₄alkyl)₂-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl-O—C₁₋₄alkyl)₂.

As used herein, the term “(C₁₋₄alkoxy-C₁₋₄alkyl)(C₁₋₄alkyl)amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl-O—C₁₋₄alkyl).

As used herein, the term “C₁₋₄alkoxy-carbonyl” refers to a radical of the formula: —C(O)—O—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkoxy-carbonyl-C₂₋₈alkenyl” refers to a radical of the formula: —C₂₋₈alkenyl-C(O)—O—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkoxy-carbonyl-amino” refers to a radical of the formula: —NH—C(O)—O—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-amino-C₂₋₈alkenyl” refers to a radical of the formula: —C₂₋₈alkenyl-NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino-C₂₋₈alkenyl” refers to a radical of the formula: —C₂₋₈alkenyl-N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-amino-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-N(C₁₋₄alkyl)₂.

As used herein, the term “(C₁₋₄alkyl-amino-C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl-NH—C₁₋₄alkyl)₂.

As used herein, the term “[(C₁₋₄alkyl)₂-amino-C₁₋₄alkyl]₂-amino” refers to a radical of the formula: —N[C₁₋₄alkyl-N(C₁₋₄alkyl)_(2]2.)

As used herein, the term “(C₁₋₄alkyl-amino-C₁₋₄alkyl)(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)(C₁₋₄alkyl-NH—C₁₋₄alkyl).

As used herein, the term “[(C₁₋₄alkyl)₂-amino-C₁₋₄alkyl](C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)[C₁₋₄alkyl-N(C₁₋₄alkyl)₂].

As used herein, the term “C₁₋₄alkyl-amino-C₂₋₈alkynyl” refers to a radical of the formula: —C₂₋₈alkynyl-NH—C₁₋₄alkyl.

As used herein, the term “(C₁₋₄alkyl)₂-amino-C₂₋₈alkynyl” refers to a radical of the formula: —C₂₋₈alkynyl-N(C₁₋₄alkyl)₂.

As used herein, the term “C₁₋₄alkyl-carbonyl” refers to a radical of the formula: —C(O)—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkyl-carbonyl-amino” refers to a radical of the formula: —NH—C(O)—C₁₋₄alkyl.

As used herein, the term “C₁₋₄alkyl-thio” refers to a radical of the formula: —S—C₁₋₄alkyl. As used herein, the term “amino-C₂₋₈alkenyl” refers to a radical of the formula: —C₂₋₈alkenyl-NH₂.

As used herein, the term “amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-NH₂.

As used herein, the term “amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH₂.

As used herein, the term “amino-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-NH₂.

As used herein, the term “(amino-C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl-NH₂)₂.

As used herein, the term “(amino-C₁₋₄alkyl)(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)(C₁₋₄alkyl-NH₂).

As used herein, the term “amino-C₂₋₈alkynyl” refers to a radical of the formula: —C₂₋₈alkynyl-NH₂.

As used herein, the term “aryl-C₁₋₄alkoxy-carbonyl” refers to a radical of the formula: —C(O)—O—C₁₋₄alkyl-aryl.

As used herein, the term “aryl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-aryl.

As used herein, the term “aryl-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-aryl.

As used herein, the term “(aryl-C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl-aryl)₂.

As used herein, the term “(aryl-C₁₋₄alkyl)(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)(C₁₋₄alkyl-aryl).

As used herein, the term “aryl-C₁₋₄alkyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH—C₁₋₄alkyl-aryl.

As used herein, the term “(aryl-C₁₋₄alkyl)₂-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl-aryl)₂.

As used herein, the term “(aryl-C₁₋₄alkyl)(C₁₋₄alkyl)amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl-aryl).

As used herein, the term “aryl-amino” refers to a radical of the formula: —NH-aryl.

As used herein, the term “aryl-amino-carbonyl” refers to a radical of the formula: —C(O)—NH-aryl.

As used herein, the term “aryl-sulfonyloxy-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-O—SO₂-aryl.

As used herein, the term “benzoxy-carbonyl” refers to a radical of the formula: —C(O)—O—CH₂-phenyl.

As used herein, the term “C₃₋₁₄cycloalkyl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-C₃₋₁₄cycloalkyl.

As used herein, the term “C₃₋₁₄cycloalkyl-amino” refers to a radical of the formula: —NH—C₃₋₁₄cycloalkyl.

As used herein, the term “C₃₋₁₄cycloalkyl-oxy” refers to a radical of the formula: —O—C₃₋₁₄cycloalkyl.

As used herein, the term “deutero-C₁₋₄alkyl,” refers to a radical of the formula: —C₁₋₄alkyl-deutero, wherein C₁₋₄alkyl is partially or completely substituted with one or more deuterium atoms where allowed by available valences.

As used herein, the term “halo” or “halogen” generally refers to a halogen atom radical, including fluoro, chloro, bromo and iodo.

As used herein, the term “halo-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-halo, wherein C₁₋₄alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.

As used herein, the term “halo-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-halo, wherein C₁₋₄alkyl is partially or completely substituted with one or more halogen atoms where allowed by available valences.

As used herein, the term “halo-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-halo.

As used herein, the term “(halo-C₁₋₄alkyl)(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)(C₁₋₄alkyl-halo).

As used herein, the term “(halo-C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl-halo)₂.

As used herein, the term “heteroaryl-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-heteroaryl.

As used herein, the term “heteroaryl-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-heteroaryl.

As used herein, the term “(heteroaryl-C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl-heteroaryl)₂.

As used herein, the term “(heteroaryl-C₁₋₄alkyl)(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)(C₁₋₄alkyl-heteroaryl).

As used herein, the term “heteroaryl-C₁₋₄alkyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH—C₁₋₄alkyl-heteroaryl.

As used herein, the term “(heteroaryl-C₁₋₄alkyl)₂-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl-heteroaryl)₂.

As used herein, the term “(heteroaryl-C₁₋₄alkyl)(C₁₋₄alkyl)amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl-heteroaryl).

As used herein, the term “heteroaryl-amino” refers to a radical of the formula: —NH-heteroaryl.

As used herein, the term “heterocyclyl-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-heterocyclyl.

As used herein, the term “heterocyclyl-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-heterocyclyl.

As used herein, the term “heterocyclyl-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-heterocyclyl.

As used herein, the term “(heterocyclyl-C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl-heterocyclyl)₂.

As used herein, the term “(heterocyclyl-C₁₋₄alkyl)(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)(C₁₋₄alkyl-heterocyclyl).

As used herein, the term “heterocyclyl-C₁₋₄alkyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH—C₁₋₄alkyl-heterocyclyl.

As used herein, the term “(heterocyclyl-C₁₋₄alkyl)₂-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl-heterocyclyl)₂.

As used herein, the term “(heterocyclyl-C₁₋₄alkyl)(C₁₋₄alkyl)amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl-heterocyclyl).

As used herein, the term “heterocyclyl-amino” refers to a radical of the formula: —NH-heterocyclyl.

As used herein, the term “(heterocyclyl)(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)(heterocyclyl).

As used herein, the term “heterocyclyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH-heterocyclyl.

As used herein, the term “heterocyclyl-carbonyl” refers to a radical of the formula: —C(O)-heterocyclyl.

As used herein, the term “heterocyclyl-carbonyl-oxy” refers to a radical of the formula: —O—C(O)-heterocyclyl.

As used herein, the term “heterocyclyl-oxy” refers to a radical of the formula: —O-heterocyclyl.

As used herein, the term “hydroxy” refers to a radical of the formula: —OH.

As used herein, the term “hydroxy-C₁₋₄alkoxy-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-O—C₁₋₄alkyl-OH.

As used herein, the term “hydroxy-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-OH, wherein C₁₋₄alkyl is partially or completely substituted with one or more hydroxy radicals where allowed by available valences.

As used herein, the term “hydroxy-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₄alkyl)(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)(C₁₋₄alkyl-OH).

As used herein, the term “hydroxy-C₁₋₄alkyl-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-NH—C₁₋₄alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₄alkyl)₂-amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₄alkyl)(C₁₋₄alkyl)amino-C₁₋₄alkyl” refers to a radical of the formula: —C₁₋₄alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl-OH).

As used herein, the term “hydroxy-C₁₋₄alkyl-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-NH—C₁₋₄alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₄alkyl)₂-amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-N(C₁₋₄alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₄alkyl)(C₁₋₄alkyl)amino-C₁₋₄alkoxy” refers to a radical of the formula: —O—C₁₋₄alkyl-N(C₁₋₄alkyl)(C₁₋₄alkyl-OH).

As used herein, the term “hydroxy-C₁₋₄alkyl-amino-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-NH—C₁₋₄alkyl-OH.

As used herein, the term “(hydroxy-C₁₋₄alkyl-amino-C₁₋₄alkyl)₂-amino” refers to a radical of the formula: —N(C₁₋₄alkyl-NH—C₁₋₄alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₄alkyl)₂-amino-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-N(C₁₋₄alkyl-OH)₂.

As used herein, the term “(hydroxy-C₁₋₄alkyl-amino-C₁₋₄alkyl)(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)(C₁₋₄alkyl-NH—C₁₋₄alkyl-OH).

As used herein, the term “[(hydroxy-C₁₋₄alkyl)₂-amino-C₁₋₄alkyl](C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)[C₁₋₄alkyl-N(C₁₋₄alkyl-OH)₂].

As used herein, the term “(hydroxy-C₁₋₄alkyl)(C₁₋₄alkyl)amino-C₁₋₄alkyl-amino” refers to a radical of the formula: —NH—C₁₋₄alkyl-N(C₁₋₄alkyl, C₁₋₄alkyl-OH).

As used herein, the term “[(hydroxy-C₁₋₄alkyl)(C₁₋₄alkyl)amino-C₁₋₄alkyl]-(C₁₋₄alkyl)amino” refers to a radical of the formula: —N(C₁₋₄alkyl)[C₁₋₄alkyl-N(C₁₋₄alkyl)-(C₁₋₄alkyl-OH)].

As used herein, the term “substituent” means positional variables on the atoms of a core molecule that are substituted at a designated atom position, replacing one or more hydrogens on the designated atom, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A person of ordinary skill in the art should note that any carbon as well as heteroatom with valences that appear to be unsatisfied as described or shown herein is assumed to have a sufficient number of hydrogen atom(s) to satisfy the valences described or shown. In certain instances one or more substituents having a double bond (e.g., “oxo” or “═O”) as the point of attachment may be described, shown or listed herein within a substituent group, wherein the structure may only show a single bond as the point of attachment to the core structure of Formula (I) or Formula (II). A person of ordinary skill in the art would understand that, while only a single bond is shown, a double bond is intended for those substituents.

As used herein, the term “and the like,” with reference to the definitions of chemical terms provided herein, means that variations in chemical structures that could be expected by one skilled in the art include, without limitation, isomers (including chain, branching or positional structural isomers), hydration of ring systems (including saturation or partial unsaturation of monocyclic, bicyclic or polycyclic ring structures) and all other variations where allowed by available valences which result in a stable compound.

For the purposes of this description, where one or more substituent variables for a compound of Formula (I) or Formula (II) or a form thereof encompass functionalities incorporated into a compound of Formula (I) or Formula (II), each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently and/or optionally substituted.

As used herein, the terms “independently selected,” or “each selected” refer to functional variables in a substituent list that may occur more than once on the structure of Formula (I) or Formula (II), the pattern of substitution at each occurrence is independent of the pattern at any other occurrence. Further, the use of a generic substituent variable on any formula or structure for a compound described herein is understood to include the replacement of the generic substituent with species substituents that are included within the particular genus, e.g., aryl may be replaced with phenyl or naphthalenyl and the like, and that the resulting compound is to be included within the scope of the compounds described herein.

As used herein, the terms “each instance of” or “in each instance, when present,” when used preceding a phrase such as “ . . . C₃₋₁₄cycloalkyl, C₃₋₁₄cycloalkyl-C₁₋₄alkyl, aryl, aryl-C₁₋₄alkyl, heteroaryl, heteroaryl-C₁₋₄alkyl, heterocyclyl and heterocyclyl-C₁₋₄alkyl,” are intended to refer to the C₃₋₁₄cycloalkyl, aryl, heteroaryl and heterocyclyl ring systems when each are present either alone or as a substituent.

As used herein, the term “optionally substituted” means optional substitution with the specified substituent variables, groups, radicals or moieties.

Compound Forms

As used herein, the term “form” means a compound of Formula (I) or Formula (II) having a form selected from the group consisting of a free acid, free base, prodrug, salt, hydrate, solvate, clathrate, isotopologue, racemate, enantiomer, diastereomer, stereoisomer, polymorph and tautomer form thereof.

In certain aspects described herein, the form of the compound of Formula (I) or Formula (II) is a free acid, free base or salt thereof.

In certain aspects described herein, the form of the compound of Formula (I) or Formula (II) is a salt thereof.

In certain aspects described herein, the form of the compound of Formula (I) or Formula (II) is an isotopologue thereof.

In certain aspects described herein, the form of the compound of Formula (I) or Formula (II) is a stereoisomer, racemate, enantiomer or diastereomer thereof.

In certain aspects described herein, the form of the compound of Formula (I) or Formula (II) is a tautomer thereof.

In certain aspects described herein, the form of the compound of Formula (I) or Formula (II) is a pharmaceutically acceptable form.

In certain aspects described herein, the compound of Formula (I) or Formula (II) or a form thereof is isolated for use.

As used herein, the term “isolated” means the physical state of a compound of Formula (I) or Formula (II) or a form thereof after being isolated and/or purified from a synthetic process (e.g., from a reaction mixture) or natural source or combination thereof according to an isolation or purification process or processes described herein or which are well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterized by standard analytical techniques described herein or well known to the skilled artisan.

As used herein, the term “protected” means that a functional group in a compound of Formula (I) or Formula (II) or a form thereof is in a form modified to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T.W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. Such functional groups include hydroxy, phenol, amino and carboxylic acid. Suitable protecting groups for hydroxy or phenol include trialkylsilyl or diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl, methoxymethanol, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. In certain instances, the protecting group may also be a polymer resin, such as a Wang resin or a 2-chlorotrityl-chloride resin. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art and as described herein. It will also be appreciated by those skilled in the art, although such protected derivatives of compounds described herein may not possess pharmacological activity as such, they may be administered to a subject and thereafter metabolized in the body to form compounds described herein which are pharmacologically active. Such derivatives may therefore be described as “prodrugs”. All prodrugs of compounds described herein are included within the scope of the use described herein.

As used herein, the term “prodrug” means a form of an instant compound (e.g., a drug precursor) that is transformed in vivo to yield an active compound of Formula (I) or Formula (II) or a form thereof. The transformation may occur by various mechanisms (e.g., by metabolic and/or non-metabolic chemical processes), such as, for example, by hydrolysis and/or metabolism in blood, liver and/or other organs and tissues. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

In one example, when a compound of Formula (I) or Formula (II) or a form thereof contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a functional group such as alkyl and the like. In another example, when a compound of Formula (I) or Formula (II) or a form thereof contains a hydroxyl functional group, a prodrug form can be prepared by replacing the hydrogen atom of the hydroxyl with another functional group such as alkyl, alkylcarbonyl or a phosphonate ester and the like. In another example, when a compound of Formula (I) or Formula (II) or a form thereof contains an amine functional group, a prodrug form can be prepared by replacing one or more amine hydrogen atoms with a functional group such as alkyl or substituted carbonyl. Pharmaceutically acceptable prodrugs of compounds of Formula (I) or Formula (II) or a form thereof include those compounds substituted with one or more of the following groups: carboxylic acid esters, sulfonate esters, amino acid esters, phosphonate esters and mono-, di- or triphosphate esters or alkyl substituents, where appropriate. As described herein, it is understood by a person of ordinary skill in the art that one or more of such substituents may be used to provide a compound of Formula (I) or Formula (II) or a form thereof as a prodrug.

One or more compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the description herein is intended to embrace both solvated and unsolvated forms.

As used herein, the term “solvate” means a physical association of a compound described herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. As used herein, “solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.

As used herein, the term “hydrate” means a solvate wherein the solvent molecule is water.

The compounds of Formula (I) or Formula (II) can form salts, which are intended to be included within the scope of this description. Reference to a compound of Formula (I) or Formula (II) or a form thereof herein is understood to include reference to salt forms thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of Formula (I) or Formula (II) or a form thereof contains both a basic moiety, such as, without limitation an amine moiety, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein.

The term “pharmaceutically acceptable salt(s)”, as used herein, means those salts of compounds described herein that are safe and effective (i.e., non-toxic, physiologically acceptable) for use in mammals and that possess biological activity, although other salts are also useful. Salts of the compounds of the Formula (I) or Formula (II) may be formed, for example, by reacting a compound of Formula (I) or Formula (II) or a form thereof with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Pharmaceutically acceptable salts include one or more salts of acidic or basic groups present in compounds described herein. Particular aspects of acid addition salts include, and are not limited to, acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, bitartrate, borate, bromide, butyrate, chloride, citrate, camphorate, camphorsulfonate, ethanesulfonate, formate, fumarate, gentisinate, gluconate, glucaronate, glutamate, iodide, isonicotinate, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phosphate, propionate, saccharate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), trifluoroacetate salts and the like. Certain particular aspects of acid addition salts include chloride or dichloride.

Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33, 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Suitable basic salts include, but are not limited to, aluminum, ammonium, calcium, lithium, magnesium, potassium, sodium and zinc salts.

All such acid salts and base salts are intended to be included within the scope of pharmaceutically acceptable salts as described herein. In addition, all such acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of this description.

Compounds of Formula (I) or Formula (II) and forms thereof, may further exist in a tautomeric form. All such tautomeric forms are contemplated and intended to be included within the scope of the compounds of Formula (I) or Formula (II) or a form thereof as described herein.

The compounds of Formula (I) or Formula (II) or a form thereof may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. The present description is intended to include all stereoisomeric forms of the compounds of Formula (I) or Formula (II) as well as mixtures thereof, including racemic mixtures.

The compounds described herein may include one or more chiral centers, and as such may exist as racemic mixtures (R S) or as substantially pure enantiomers and diastereomers. The compounds may also exist as substantially pure (R) or (S) enantiomers (when one chiral center is present). In one particular aspect, the compounds described herein are (S) isomers and may exist as enantiomerically pure compositions substantially comprising only the (S) isomer. In another particular aspect, the compounds described herein are (R) isomers and may exist as enantiomerically pure compositions substantially comprising only the (R) isomer. As one of skill in the art will recognize, when more than one chiral center is present, the compounds described herein may also exist as a (R,R), (R,S), (S,R) or (S,S) isomer, as defined by IUPAC Nomenclature Recommendations.

As used herein, the term “substantially pure” refers to compounds consisting substantially of a single isomer in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100% of the single isomer.

In one aspect of the description, a compound of Formula (I) or Formula (II) or a form thereof is a substantially pure (S) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

In one aspect of the description, a compound of Formula (I) or Formula (II) or a form thereof is a substantially pure (R) enantiomer form present in an amount greater than or equal to 90%, in an amount greater than or equal to 92%, in an amount greater than or equal to 95%, in an amount greater than or equal to 98%, in an amount greater than or equal to 99%, or in an amount equal to 100%.

As used herein, a “racemate” is any mixture of isometric forms that are not “enantiomerically pure”, including mixtures such as, without limitation, in a ratio of about 50/50, about 60/40, about 70/30, or about 80/20.

In addition, the present description embraces all geometric and positional isomers. For example, if a compound of Formula (I) or Formula (II) or a form thereof incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the description. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by use of chiral HPLC column or other chromatographic methods known to those skilled in the art. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) or Formula (II) may be atropisomers (e.g., substituted biaryls) and are considered as part of this description.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this description, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). Individual stereoisomers of the compounds described herein may, for example, be substantially free of other isomers, or may be present in a racemic mixture, as described supra.

The use of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or isotopologues of the instant compounds.

The term “isotopologue” refers to isotopically-enriched compounds described herein which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁵Cl and ³⁶Cl, respectively, each of which are also within the scope of this description.

Certain isotopically-enriched compounds described herein (e.g., those labeled with ³H and ¹⁴C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.

Polymorphic crystalline and amorphous forms of the compounds of Formula (I) or Formula (II) and of the salts, solvates, hydrates, esters and prodrugs of the compounds of Formula (I) or Formula (II) are further intended to be included in the present description.

Compound Uses

In accordance with the intended scope of the present description, aspects of the present description include compounds that have been identified and have been demonstrated to be useful in selectively preventing, treating or ameliorating HD and have been provided for use for preventing, treating or ameliorating HD.

An aspect of the present description includes a method for preventing, treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a method for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a method for preventing HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a method for treating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a method for ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound of Formula (I) or Formula (II) or a form thereof.

Another aspect of the present description includes a method for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of a compound salt of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a method for use of a compound of Formula (I) or Formula (II) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form or composition thereof.

Another aspect of the present description includes a method for use of a compound salt of Formula (I) or Formula (II) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof.

Another aspect of the present description includes a use for a compound salt of Formula (I) or Formula (II) or a form thereof for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

Another aspect of the present description includes a use for a compound salt of Formula (I) or Formula (II) or a form thereof in the manufacture of a medicament for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the medicament.

An aspect of the present description includes in vitro or in vivo use of the compound of Formula (I) or Formula (II) or a form thereof having activity toward HD.

An aspect of the present description includes a use of the compound of Formula (I) or Formula (II) or a form thereof in a combination therapy to provide additive or synergistic activity, thus enabling the development of a combination product for treating or ameliorating HD.

Another aspect of the present description includes a combination therapy comprising compounds described herein in combination with one or more known drugs or one or more known therapies may be used to treat HD regardless of whether HD is responsive to the known drug.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof in combination with an effective amount of the one or more agents.

Another aspect of the present description includes a use for a compound salt of Formula (I) or Formula (II) or a form thereof in a combination product with one or more therapeutic agents for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound salt of Formula (I) or Formula (II) or a form thereof in combination with an effective amount of the one or more agents.

In an aspect of a use or method provided herein, compounds of Formula (I) or Formula (II) or a form thereof used in combination with one or more additional agents can be administered to a subject or contacted with a subject or patient cell(s) prior to, concurrently with, or subsequent to administering to the subject or patient or contacting the cell with an additional agent(s). A compound(s) of Formula (I) or Formula (II) or a form thereof and an additional agent(s) can be administered to a subject or contacted with a cell in single composition or different compositions. In a specific aspect, a compound(s) of Formula (I) or Formula (II) or a form thereof is used in combination with gene therapy to inhibit HTT expression (using, e.g., viral delivery vectors) or the administration of another small molecule HTT inhibitor. In another specific aspect, a compound(s) of Formula (I) or Formula (II) or a form thereof are used in combination with cell replacement using differentiated non-mutant HTT stem cells. In another specific aspect, a compound(s) of Formula (I) or Formula (II) or a form thereof are used in combination with cell replacement using differentiated HTT stem cells.

In one aspect, provided herein is the use of compounds of Formula (I) or Formula (II) or a form thereof in combination with supportive standard of care therapies, including palliative care.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in the preparation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the compound of Formula (I) or Formula (II) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in the preparation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the compound of Formula (I) or Formula (II) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof; and optionally, for administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof in a combination product with an effective amount of one or more therapeutic agents.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in the preparation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the compound of Formula (I) or Formula (II) or a form thereof and instructions for administering an effective amount of the compound of Formula (I) or Formula (II) or a form thereof; and optionally, for administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof in a combination product with an effective amount of the one or more therapeutic agents; and optionally, for administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof in a combination product with an effective amount of the one or more therapeutic agents in a combination therapy with a standard of care supportive therapy, wherein the standard of care supportive therapy is palliative care.

In one respect, for each of such aspects, the subject is treatment naive. In another respect, for each of such aspects, the subject is not treatment naive.

As used herein, the term “preventing” refers to keeping a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having the disease, disorder and/or condition.

As used herein, the term “treating” refers to inhibiting the progression of a disease, disorder or condition in a subject already exhibiting the symptoms of the disease, disorder and/or condition, i.e., arresting the development of a disease, disorder and/or condition that has already affected the subject.

As used herein, the term “ameliorating” refers to relieving the symptoms of a disease, disorder or condition in a subject already exhibiting the symptoms of the disease, disorder and/or condition, i.e., causing regression of the disease, disorder and/or condition that has already affected the subject.

As used herein, the term “subject” refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires oxygen and organic food. Nonlimiting examples include members of the human, primate, equine, porcine, bovine, murine, rattus, canine and feline specie. In certain aspects, the subject is a mammal or a warm-blooded vertebrate animal. In other aspects, the subject is a human. As used herein, the term “patient” may be used interchangeably with “subject” and “human”.

As used herein, the terms “effective amount” or “therapeutically effective amount” mean an amount of compound of Formula (I) or Formula (II) or a form, composition or medicament thereof that achieves a target plasma concentration that is effective in treating or ameliorating HD as described herein and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect in a subject in need thereof. In one aspect, the effective amount may be the amount required to treat HD in a subject or patient, more specifically, in a human.

In another aspect, the concentration-biological effect relationships observed with regard to a compound of Formula (I) or Formula (II) or a form thereof indicate a target plasma concentration ranging from approximately 0.001 μg/mL to approximately 50 μg/mL, from approximately 0.01 μg/mL to approximately 20 μg/mL, from approximately 0.05 μg/mL to approximately 10 μg/mL, or from approximately 0.1 μg/mL to approximately 5 μg/mL. To achieve such plasma concentrations, the compounds described herein may be administered at doses that vary, such as, for example, without limitation, from 1.0 ng to 10,000 mg.

In one aspect, the dose administered to achieve an effective target plasma concentration may be administered based upon subject or patient specific factors, wherein the doses administered on a weight basis may be in the range of from about 0.001 mg/kg/day to about 3500 mg/kg/day, or about 0.001 mg/kg/day to about 3000 mg/kg/day, or about 0.001 mg/kg/day to about 2500 mg/kg/day, or about 0.001 mg/kg/day to about 2000 mg/kg/day, or about 0.001 mg/kg/day to about 1500 mg/kg/day, or about 0.001 mg/kg/day to about 1000 mg/kg/day, or about 0.001 mg/kg/day to about 500 mg/kg/day, or about 0.001 mg/kg/day to about 250 mg/kg/day, or about 0.001 mg/kg/day to about 200 mg/kg/day, or about 0.001 mg/kg/day to about 150 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day, or about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 50 mg/kg/day, or about 0.001 mg/kg/day to about 25 mg/kg/day, or about 0.001 mg/kg/day to about 10 mg/kg/day, or about 0.001 mg/kg/day to about 5 mg/kg/day, or about 0.001 mg/kg/day to about 1 mg/kg/day, or about 0.001 mg/kg/day to about 0.5 mg/kg/day, or about 0.001 mg/kg/day to about 0.1 mg/kg/day, or from about 0.01 mg/kg/day to about 3500 mg/kg/day, or about 0.01 mg/kg/day to about 3000 mg/kg/day, or about 0.01 mg/kg/day to about 2500 mg/kg/day, or about 0.01 mg/kg/day to about 2000 mg/kg/day, or about 0.01 mg/kg/day to about 1500 mg/kg/day, or about 0.01 mg/kg/day to about 1000 mg/kg/day, or about 0.01 mg/kg/day to about 500 mg/kg/day, or about 0.01 mg/kg/day to about 250 mg/kg/day, or about 0.01 mg/kg/day to about 200 mg/kg/day, or about 0.01 mg/kg/day to about 150 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day, or about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 50 mg/kg/day, or about 0.01 mg/kg/day to about 25 mg/kg/day, or about 0.01 mg/kg/day to about 10 mg/kg/day, or about 0.01 mg/kg/day to about 5 mg/kg/day, or about 0.01 mg/kg/day to about 1 mg/kg/day, or about 0.01 mg/kg/day to about 0.5 mg/kg/day, or about 0.01 mg/kg/day to about 0.1 mg/kg/day, or from about 0.1 mg/kg/day to about 3500 mg/kg/day, or about 0.1 mg/kg/day to about 3000 mg/kg/day, or about 0.1 mg/kg/day to about 2500 mg/kg/day, or about 0.1 mg/kg/day to about 2000 mg/kg/day, or about 0.1 mg/kg/day to about 1500 mg/kg/day, or about 0.1 mg/kg/day to about 1000 mg/kg/day, or about 0.1 mg/kg/day to about 500 mg/kg/day, or about 0.1 mg/kg/day to about 250 mg/kg/day, or about 0.1 mg/kg/day to about 200 mg/kg/day, or about 0.1 mg/kg/day to about 150 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day, or about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 50 mg/kg/day, or about 0.1 mg/kg/day to about 25 mg/kg/day, or about 0.1 mg/kg/day to about 10 mg/kg/day, or about 0.1 mg/kg/day to about 5 mg/kg/day, or about 0.1 mg/kg/day to about 1 mg/kg/day, or about 0.1 mg/kg/day to about 0.5 mg/kg/day.

Effective amounts for a given subject may be determined by routine experimentation that is within the skill and judgment of a clinician or a practitioner skilled in the art in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include genetic screening, severity of the disease state, status of disease progression, general health of the subject, ethnicity, age, weight, gender, diet, time of day and frequency of administration, drug combination(s), reaction sensitivities, experience with other therapies, and tolerance/response to therapy.

The dose administered to achieve an effective target plasma concentration may be orally administered once (once in approximately a 24 hour period; i.e., “q.d.”), twice (once in approximately a 12 hour period; i.e., “b.i.d.” or “q.12h”), thrice (once in approximately an 8 hour period; i.e., “t.i.d.” or “q.8h”), or four times (once in approximately a 6 hour period; i.e., “q.d.s.”, “q.i.d.” or “q.6h”) daily.

In certain aspects, the dose administered to achieve an effective target plasma concentration may also be administered in a single, divided, or continuous dose for a patient or subject having a weight in a range of between about 40 to about 200 kg (which dose may be adjusted for patients or subjects above or below this range, particularly children under 40 kg). The typical adult subject is expected to have a median weight in a range of about 70 kg. Long-acting pharmaceutical compositions may be administered every 2, 3 or 4 days, once every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

The compounds and compositions described herein may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, sublingual, transdermal, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, and pulmonary routes of administration.

In another aspect, the dose administered may be adjusted based upon a dosage form described herein formulated for delivery at about 0.02, 0.025, 0.03, 0.05, 0.06, 0.075, 0.08, 0.09, 0.10, 0.20, 0.25, 0.30, 0.50, 0.60, 0.75, 0.80, 0.90, 1.0, 1.10, 1.20, 1.25, 1.50, 1.75, 2.0, 3.0, 5.0, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 400, 500, 1000, 1500, 2000, 2500, 3000 or 4000 mg/day.

For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as a mouse, guinea pig, chimpanzee, marmoset or tamarin animal model. Relevant animal models may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is therapeutic index, and can be expressed as the ratio, LD₅₀/ED₅₀. In certain aspects, the effective amount is such that a large therapeutic index is achieved. In further particular aspects, the dosage is within a range of circulating concentrations that include an ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

In one aspect, provided herein are methods for modulating the amount of HTT (huntingtin protein), comprising contacting a human cell with a compound of Formula (I) or Formula (II) or a form thereof. In a specific aspect, provided herein are methods for modulating the amount of HTT, comprising contacting a human cell with a compound of Formula (I) or Formula (II) or a form thereof that modulates the expression of HTT. The human cell can be contacted with a compound of Formula (I) or Formula (II) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific aspect, the human cell is from or in a human. In another specific aspect, the human cell is from or in a human with HD. In another specific aspect, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of HTT expression and/or function. In another aspect, the human cell is from a human with HD. In another aspect, the human cell is in a human with HD. In one aspect, the compound is a form of the compound of Formula (I) or Formula (II).

In a specific aspect, provided herein is a method for enhancing the inhibition of mutant HTT transcribed from the Htt gene, comprising contacting a human cell with a compound of Formula (I) or Formula (II) or a form thereof. The human cell can be contacted with a compound of Formula (I) or Formula (II) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific aspect, the human cell is from or in a human. In another specific aspect, the human cell is from or in a human with HD. In another specific aspect, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of wild-type “normal” HTT expression and/or function. In another aspect, the human cell is from a human with HD. In another aspect, the human cell is in a human with HD. In one aspect, the compound is a form of the compound of Formula (I) or Formula (II).

In another aspect, provided herein is a method for modulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering to a non-human animal model for HD a compound of Formula (I) or Formula (II) or a form thereof. In a specific aspect, provided herein is a method for modulating the inhibition of mutant HTT transcribed from the Htt gene, comprising administering to a non-human animal model for HD a compound of Formula (I) or Formula (II) or a form thereof. In a specific aspect, the compound is a form of the compound of Formula (I) or Formula (II).

In another aspect, provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I) or Formula (II) or a form thereof. In a specific aspect, provided herein is a method for decreasing the amount of mutant HTT, comprising contacting a human cell with a compound of Formula (I) or Formula (II) that inhibits the transcription of mutant HTT (huntingtin mRNA) from the Htt gene. In another specific aspect, provided herein is a method for decreasing the amount of HTT, comprising contacting a human cell with a compound of Formula (I) or Formula (II) that inhibits the expression of mutant HTT transcribed from the Htt gene. The human cell can be contacted with a compound of Formula (I) or Formula (II) or a form thereof in vitro, or in vivo, e.g., in a non-human animal or in a human. In a specific aspect, the human cell is from or in a human. In another specific aspect, the human cell is from or in a human with HD. In another specific aspect, the human cell is from or in a human with HD, caused by a CAG repeat in the Htt gene, resulting in a loss of HTT expression and/or function. In another aspect, the human cell is from a human with HD. In another aspect, the human cell is in a human with HD. In one aspect, the compound is a form of the compound of Formula (I) or Formula (II).

In certain aspects, treating or ameliorating HD with a compound of Formula (I) or Formula (II) or a form thereof (alone or in combination with an additional agent) has a therapeutic effect and/or beneficial effect. In a specific aspect, treating HD with a compound of Formula (I) or Formula (II) or a form thereof (alone or in combination with an additional agent) results in one, two or more of the following effects: (i) reduces or ameliorates the severity of HD; (ii) delays onset of HD; (iii) inhibits the progression of HD; (iv) reduces hospitalization of a subject; (v) reduces hospitalization length for a subject; (vi) increases the survival of a subject; (vii) improves the quality of life for a subject; (viii) reduces the number of symptoms associated with HD; (ix) reduces or ameliorates the severity of a symptom(s) associated with HD; (x) reduces the duration of a symptom associated with HD; (xi) prevents the recurrence of a symptom associated with HD; (xii) inhibits the development or onset of a symptom of HD; and/or (xiii) inhibits of the progression of a symptom associated with HD.

Metabolites

Another aspect included within the scope of the present description are the use of in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the description includes the use of compounds produced by a process comprising contacting a compound described herein with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.

Such products typically are identified by preparing a radio-labeled isotopologue (e.g., ¹C or ³H) of a compound described herein, administering the radio-labeled compound in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as a rat, mouse, guinea pig, dog, monkey or human, allowing sufficient time for metabolism to occur (typically about 30 seconds to about 30 hours), and identifying the metabolic conversion products from urine, bile, blood or other biological samples. The conversion products are easily isolated since they are “radiolabeled” by virtue of being isotopically-enriched (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds described herein even if they possess no biological activity of their own.

Pharmaceutical Compositions

In accordance with the intended scope of the present description, aspects of the present description include compounds that have been identified and have been demonstrated to be useful in selectively preventing, treating or ameliorating HD and have been provided for use as one or more pharmaceutical compositions for preventing, treating or ameliorating HD.

An aspect of the present description includes a use for a compound of Formula (I) or Formula (II) or a form thereof in the preparation of a pharmaceutical composition for treating or ameliorating HD in a subject in need thereof comprising, administering to the subject an effective amount of the compound of Formula (I) or Formula (II) or a form thereof in admixture with one or more pharmaceutically acceptable excipients.

An aspect of the present description includes a use for a pharmaceutical composition of the compound of Formula (I) or Formula (II) or a form thereof in the preparation of a kit for treating or ameliorating HD in a subject in need thereof comprising, the pharmaceutical composition of the compound of Formula (I) or Formula (II) or a form thereof and instructions for administering the pharmaceutical composition.

As used herein, the term “composition” means a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The pharmaceutical composition may be formulated to achieve a physiologically compatible pH, ranging from about pH 3 to about pH 11. In certain aspects, the pharmaceutical composition is formulated to achieve a pH of from about pH 3 to about pH 7. In other aspects, the pharmaceutical composition is formulated to achieve a pH of from about pH 5 to about pH 8.

The term “pharmaceutically acceptable excipient” refers to an excipient for administration of a pharmaceutical agent, such as the compounds described herein. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form. Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions for the instant compounds described herein (see, e.g., Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive antibodies. Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose (e.g., hydroxypropylmethylcellulose, also known as HPMC), stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described herein may be formulated in any form suitable for the intended use described herein. Suitable formulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhalable formulations for pulmonary administration include liquids and powders. Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.

When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to provide a palatable preparation.

Pharmaceutically acceptable excipients suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin, or olive oil.

In other aspects, pharmaceutical compositions described herein may be formulated as suspensions comprising a compound of Formula (I) or Formula (II) or a form thereof in admixture with one or more pharmaceutically acceptable excipients suitable for the manufacture of a suspension. In yet other aspects, pharmaceutical compositions described herein may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipients.

Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.

The pharmaceutical compositions described herein may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

Additionally, the pharmaceutical compositions described herein may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The compounds described herein may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, but generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the description are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.

In certain aspects, the compound described herein is formulated for oral administration in a lipid-based composition suitable for low solubility compounds. Lipid-based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions described herein may comprise a effective amount of a compound of Formula (I) or Formula (II) or a form thereof, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharmaceutically acceptable surfactants, such as polysorbate 20 or 80 (also referred to as Tween® 20 or Tween® 80, respectively) or polyoxyl 40 hydrogenated castor oil.

In other aspects, the bioavailability of low solubility compounds may be enhanced using particle size optimization techniques including the preparation of nanoparticles or nanosuspensions using techniques known to those skilled in the art. The compound forms present in such preparations include amorphous, partially amorphous, partially crystalline or crystalline forms.

In alternative aspects, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and T-cyclodextrin, and hydroxypropyl-β-cyclodextrin (HIPBC). In certain aspects, the pharmaceutical composition further comprises HPBC in a range of from about 0.1% to about 20%, from about 1% to about 15%, or from about 2.5% to about 10%. The amount of solubility enhancer employed may depend on the amount of the compound in the composition.

Preparation of Compounds General Synthetic Methods

As disclosed herein, general methods for preparing the compounds of Formula (I) or Formula (II) or a form thereof as described herein are available via standard, well-known synthetic methodology. Many of the starting materials are commercially available or, when not available, can be prepared using the routes described below using techniques known to those skilled in the art. The synthetic schemes provided herein comprise multiple reaction steps, each of which is intended to stand on its own and can be carried out with or without any preceding or succeeding step(s). In other words, each of the individual reaction steps of the synthetic schemes provided herein in isolation is contemplated.

Compounds of Formula (I), wherein B is heterocyclyl, X is O, NH or NR_(1b), where R_(1b) is C₁₋₄alkyl, may be prepared as described in Scheme A below. Compound A1 (where W₁ is bromine, chlorine and the like) is converted to Compound A2 by a nucleophilic substitution with a primary or secondary amine or an alcohol (BXH) in the presence of a suitable base (such as Et₃N and the like) in a suitable solvent (such as DMF and the like). Alternatively, Compound A1 is converted to Compound A2 via cross coupling with a primary or a secondary amine in the presence of a suitable catalyst (such as RuPhos Pd G2 and the like) and base (such as sodium tert-butoxide and the like) in an appropriate solvent such as 1,4-dioxane and the like). Compound A2 is converted to Compound A3 by halogenation upon treatment with an appropriate reagent (such as bromine and the like) in an appropriate solvent (such as methanol and the like). Compound A3 is converted to Compound A4 by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)Cl₂ and the like) and base (such as aqueous K₂CO₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, Compound A3 is converted to Compound A4 by a Stille coupling with an aryl- or heteroaryl-stannane in the presence of a catalyst (such as Pd₂(dba)₃ and the like), a ligand (such as X-Phos and the like) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Any protecting groups may be removed upon treatment with a suitable reagent (such as HCl in dioxane for a Boc protecting group and the like) in a suitable solvent (such as dioxane and the like).

Compounds of Formula (I), wherein (R₄)_(n) is hydrogen, halogen, hydroxy, or C₁₋₄alkoxy, n is 0 or 1, R₄ is heterocyclyl, heteroaryl, or phenyl, B is heterocyclyl; X is O, NH or NR_(1b), and R_(1b) is C₁₋₄alkyl, may be prepared as described in Scheme B below.

Compound B1 (where W₁ is bromine, chlorine and the like) is converted to Compound B3 by a Suzuki coupling with an aryl-boronic acid (or pinacol boronic ester) B2 (where W₂ is bromine, chlorine and the like; (R₄)_(n) is hydrogen, halogen, hydroxy, or C₁₋₄alkoxy, and PG is a protecting group such as MOM and the like) in the presence of a catalyst (such as Pd(dppf)Cl₂ and the like) and base (such as aqueous K₂CO₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound B3 is converted to Compound B4 by treatment with an oxidizing agent (such as mCPBA or oxone and the like) in a suitable solvent (such as dichloromethane and the like). Compound B4 is converted to Compound B5 by a nucleophilic substitution with a primary or a secondary amine or an alcohol (BXH, where X is O, NH or NR_(1b), where R_(1b) is C₁₋₄alkyl) in the presence of a suitable base (such as Et₃N and the like) in a suitable solvent (such as DMF and the like). Compound B5 is converted to Compound B6 by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)Cl₂ and the like) and a base (such as aqueous K₂CO₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, Compound B5 is converted to Compound B6 by a Stille coupling with an aryl- or heteroaryl-stannane in the presence of a catalyst (such as Pd₂(dba)₃ and the like), a ligand (such as X-Phos and the like) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, Compound B5 is converted to Compound B6 by treatment with pinacolatodiboron and a base (such as KOAc and the like) in the presence of a catalyst (such as Pd(dppf)Cl₂ and the like) in an appropriate solvent (such as 1,4-dioxane and the like), followed by addition of an aryl- or heteroaryl-halide. Alternatively, Compound B5 is converted to Compound B6 by a Buchwald-Hartwig coupling with a heteroaryl or amine in the presence of a catalyst (such as Pd₂(dba)₃ and the like), a ligand (such as tBuX-Phos and the like) and a base (such as K₃PO₄ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound B6 is converted to Compound B7 upon treatment with conditions appropriate to the removal of the protecting groups (such as HCl in dioxane for a MOM protecting group) in a suitable solvent (such as dioxane and the like).

Following the general conditions described in Scheme B, but changing the order of steps 2 and 4, compound C1 can be converted to compound C7.

Compounds of Formula (II), wherein (R₄)_(n) is hydrogen, halogen, hydroxy, or C₁₋₄alkoxy, n is 0 or 1, R₄ is heterocyclyl, heteroaryl, or phenyl, B is heterocyclyl; X is O, NH or NR_(1b), and R_(1b) is C₁₋₄alkyl, may be prepared as described in Scheme D below.

Compound D1 (where W₁, is bromine, chlorine and the like; (R₄)_(n) is hydrogen, halogen, hydroxy, or C₁₋₄alkoxy; and PG is a protecting group such as MOM and the like) is converted to Compound D2 by a condensation/cyclization sequence in presence of hydrazine in a suitable solvent (such as ethanol and the like). Compound D2 is converted to Compound D3 by treatment with a dehydrative halogenating agent (such as POCl₃ and the like) followed by treatment with an oxidizing agent (such as manganese dioxide and the like). Compound D3 is converted to Compound D4 by a nucleophilic substitution with a primary or a secondary amine or an alcohol (BXH, where X is O, NH or NR_(1b), where R_(1b) is C₁₋₄alkyl) in the presence of a suitable base (such as Et₃N and the like) in a suitable solvent (such as DMF and the like). Alternatively, Compound D3 is converted to Compound D4 via cross coupling with a primary amine or a secondary amine or an alcohol in the presence of a suitable catalyst (such as RuPhos Pd G2 and the like) and base (such as sodium tert-butoxide and the like) in an appropriate solvent such as 1,4-dioxane and the like). Compound D4 is converted to Compound D5 by a Suzuki coupling with an aryl- or heteroaryl-boronic acid (or pinacol boronic ester) in the presence of a catalyst (such as Pd(dppf)Cl₂ and the like) and base (such as aqueous K₂CO₃ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, Compound D4 is converted to Compound D5 by a Stille coupling with an aryl- or heteroaryl-stannane in the presence of a catalyst (such as Pd₂(dba)₃ and the like), a ligand (such as X-Phos and the like) and a base (such as CsF and the like) in a suitable solvent (such as 1,4-dioxane and the like). Alternatively, Compound D4 is converted to Compound D5 by treatment with pinacolatodiboron and a base (such as KOAc and the like) in the presence of a catalyst (such as Pd(dppf)Cl₂ and the like) in an appropriate solvent (such as 1,4-dioxane and the like), followed by addition of an aryl- or heteroaryl-halide. Alternatively, Compound D4 is converted to Compound D5 by a Buchwald-Hartwig coupling with a heteroaryl or amine in the presence of a catalyst (such as Pd₂(dba)₃ and the like), a ligand (such as tBuX-Phos and the like) and a base (such as K₃PO₄ and the like) in a suitable solvent (such as 1,4-dioxane and the like). Compound D5 is converted to Compound D6 upon treatment with conditions appropriate to the removal of the protecting groups (such as HCl in dioxane for a MOM protecting group) in a suitable solvent (such as dioxane and the like).

SPECIFIC SYNTHETIC EXAMPLES

To describe in more detail and assist in understanding, the following non-limiting examples are offered to more fully illustrate the scope of compounds described herein and are not to be construed as specifically limiting the scope thereof. Such variations of the compounds described herein that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the compounds as described herein and hereinafter claimed. These examples illustrate the preparation of certain compounds. Those of skill in the art will understand that the techniques described in these examples represent techniques, as described by those of ordinary skill in the art, that function well in synthetic practice, and as such constitute preferred modes for the practice thereof. However, it should be appreciated that those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific methods that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present description.

Other than in the following examples of the embodied compounds, unless indicated to the contrary, all numbers expressing quantities of ingredients, reaction conditions, experimental data, and so forth used in the specification and claims are to be understood as being modified by the term “about”. Accordingly, all such numbers represent approximations that may vary depending upon the desired properties sought to be obtained by a reaction or as a result of variable experimental conditions. Therefore, within an expected range of experimental reproducibility, the term “about” in the context of the resulting data, refers to a range for data provided that may vary according to a standard deviation from the mean. As well, for experimental results provided, the resulting data may be rounded up or down to present data consistently, without loss of significant figures. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and rounding techniques used by those of skill in the art.

While the numerical ranges and parameters setting forth the broad scope of the present description are approximations, the numerical values set forth in the examples set forth below are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

The starting materials used in the examples provided are commercially available or can be prepared according to methods known to one skilled in the art or can be prepared by the procedures disclosed herein.

Compound Examples

As used above, and throughout the present description, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:

Abbreviation Meaning Δ heating (chemistry) or deletion (biology) AcOH or HOAc acetic acid Ar argon ACN or CH₃CN acetonitrile aq. aqueous atm atmosphere(s) BBr₃ boron tribromide B₂pin₂ bis(pinacolato)diboron Boc tert-butoxy-carbonyl t-Bu tert-butyl t-BuOK or KOtBu postassium tert-butoxide BuOH or n-BuOH n-butanol ° C. degrees Centigrade Celite ® or Celite diatomaceous earth d/h/hr/hrs/min/s day(d)/hour(h, hr or hrs)/minute(min)/ second(s) DCM or CH₂Cl₂ dichloromethane DMF dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EtOH ethanol Et₂O diethyl ether equiv equivalents H₂ hydrogen HBr hydrobromic acid HCl hydrochloric acid H₂SO₄ sulfuric acid K₂CO₃ potassium carbonate KOAc potassium acetate KOH potassium hydroxide LC/MS, LCMS or liquid chromatographic mass spectroscopy LC-MS LiOt-Bu lithium tert-butoxide LiOH lithium hydroxide mCPBA meta-chloroperoxybenzoic acid MeOH methanol MeSO₃H methanesulfonic acid MgSO₄ magnesium sulfate mL milliliter MOM methoxymethyl MS mass spectroscopy NEt₃ triethylamine NH₄Cl ammonium chloride NH₄OAc ammonium acetate Na₂CO₃ sodium carbonate NaH sodium hydride NaHCO₃ sodium bicarbonate NaOH sodium hydroxide Na₂SO₄ sodium sulfate N₂ nitrogen NH₄Cl ammoniuim chloride NMP N-methylpyrrolidone NMR nuclear magnetic resonance Pd palladium Pd/C palladium on carbon Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl₂ or [1,1′- Pd(dppf)Cl₂—CH₂Cl₂ bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane PhMe toluene Psi pounds per square inch pressure QPhos 1,2,3,4,5-pentaphenyl-1′- (di-tert-butylphosphino)ferrocene Rt or rt room temperature S-Phos, SPhos or 2-dicyclohexylphosphino-2′,6′- Sphos dimethoxybiphenyl S-Phos G₂ chloro(2-dicyclohexylphosphino-2′,6′- dimethoxy-1,1′-biphenyl)(2′-amino-1,1′- biphenyl-2-yl) palladium(II) TBAF tetrabutylammonium fluoride TBS tert-butyldimethylsilyl TEA, Et₃N or NEt₃ triethylamine Tf trifluoromethane sulfonyl or triflate TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyranyl TIPS tiisopropylsilane TLC thin layer chromatography UPLC Ulta performance liquid chromatography

Preparation of Starting Material: 4-(3-(Methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

Step 1:

2-Bromo-5-iodophenol (54.9 g, 184 mmol), was dissolved in DMF (240 mL) at 0° C. Sodium tert-pentoxide (2.5 M in THF, 90 mL, 230 mmol) was added dropwise. This was stirred at 0° C. for 15 minutes after addition was complete. Chloromethyl methyl ether (18 mL, 225 mmol) was added dropwise over 30 minutes. The mixture was warmed to ambient temperature and was stirred for 16 hours. The mixture was diluted with 1.5 L of H₂O and was extracted into 2×400 mL of EtOAc. The combined organic layers were washed with 300 mL of H₂O, and then with brine. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The residue was flushed through a silica plug using 0-10% CH₂Cl₂ in hexanes to yield 1-bromo-4-iodo-2-(methoxymethoxy)benzene (61 g, 97%) as a clear liquid.

¹H NMR (acetone-d₆): δ 7.56 (d, J=2 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.33 (dd, J=8 Hz, 2 Hz, 1H), 5.35 (s, 2H), 3.50 (s, 3H).

Step 2:

1-Bromo-4-iodo-2-(methoxymethoxy)benzene (49 g, 143 mmol), 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (48.4 g, 174 mmol), Pd(dppf)Cl₂-dichloromethane adduct (3.1 g, 3.6 mmol), dioxane (500 mL), and aqueous K₂CO₃ (1M, 350 mL, 350 mmol) were heated at 90° C. for 2 hours. The reaction mixture was then partitioned between H₂O and EtOAc. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (20-50% EtOAc), followed by trituration with hexanes, yielding 4-(4-bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (40.4 g, 77% yield) as an off-white solid.

¹H NMR (acetone-d₆): δ 8.22 (s, 1H), 7.88 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.47 (d, J=2 Hz, 1H), 7.23 (dd, J=8.5 Hz, 2 Hz, 1H), 5.44 (dd, J=9.5 Hz, 2.5 Hz, 1H), 5.38 (s, 2H), 4.01 (m, 1H), 3.72 (m, 1H), 3.51 (s, 3H), 2.1-2.23 (m, 1H), 2.0-2.1 (m, 2H), 1.7-1.8 (m, 1H), 1.6-1.7 (m, 2H).

Step 3:

A flask containing potassium acetate (22 g, 224 mmol) was pumped dry at 180° C. for 2 hours, and then was filled with argon. 4-(4-Bromo-3-(methoxymethoxy)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (20 g, 54.5 mmol), Pd(dppf)Cl₂-dichloromethane adduct (1.22 g, 1.47 mmol), bis(pinacolato)diboron (20.8 g, 81.9 mmol), and dry toluene (200 mL) were added. This mixture was heated at 110° C. for 48 h. After cooling, the mixture was filtered through celite, followed by rinsing with ether. The filtrate was concentrated under vacuum, re-dissolved in ether, and was filtered again through celite to remove solid impurities. Purification by silica gel chromatography eluting with a gradient of EtOAc/hexane (20-50% EtOAc) yielded 12 g of crude title product. The crude material was dissolved in 100 mL ether and was back-washed with 2×1.5 L of dilute aqueous NaHCO₃. The ether layer was washed with brine, dried over MgSO₄, and was filtered. The filtrate was concentrated to a glassy semi-solid. This material was hexane-triturated to yield 4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole as a white crystalline solid (7.05 g, 32% yield).

¹H NMR (acetone-d₆): δ 8.24 (s, 1H), 7.90 (s, 1H), 7.65 (d, J=8 Hz, 1H), 7.33 (d, J=1.5 Hz, 1H), 7.29 (dd, J=8 Hz, 1.5 Hz, 1H), 5.45 (dd, J=10 Hz, 2.5 Hz, 1H), 5.25 (s, 2H), 4.01 (m, 1H), 3.69-3.74 (m, 1H), 3.52 (s, 3H), 2.15-2.2 (m, 1H), 2.0-2.1 (m, 2H), 1.7-1.8 (m, 1H), 1.6-1.68 (m, 2H), 1.35 (s, 12H).

Using the procedure described, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Structure Data

MS m/z 345.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 7.94-8.03 (m, 1H), 7.84 (s, 1H), 7.64 (br d, J = 7.6 Hz, 1H), 7.25 (s, 1H), 7.20 (d, J = 7.3 Hz, 1H), 5.25 (s, 2H), 3.81-3.98 (m, 3H), 3.53 (s, 3H), 1.36 (s, 12H)

MS m/z 348.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.00 (s, 1H), 7.85 (s, 1H), 7.64 (br d, J = 7.6 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.26 (s, 2H), 4.86 (s, 3H), 1.37 (s, 12H)

MS m/z 349.2 [M − THP + H]⁺

MS m/z 316.6 [M + H]⁺

Preparation of Starting Material: 1-(3-(Methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methyl-1H-imidazole

Step 1:

An oven-dried vial was equipped with a magnetic stir bar and charged with 1-bromo-4-iodo-2-(methoxymethoxy)benzene (0.7 g, 2.0 mmol), 4-methyl-1H-imidazole (0.2 g, 2.4 mmol), copper(I) oxide (0.015 g, 0.1 mmol), salicylaldoxime (0.057 g, 0.43 mmol), and cesium carbonate (1.35 g, 4.1 mmol). The reaction mixture was purged with argon, acetonitrile (6 mL) was added, and the reaction was stirred at 50° C. for 24 h. The reaction was diluted with water and then extracted with CH₂C2. The organic layer was washed with water, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude oil was purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0-15% MeOH) to afford 1-(4-bromo-3-(methoxymethoxy)phenyl)-4-methyl-1H-imidazole (0.38 g, 1.28 mmol, 60%). MS m/z 297.1, 299.1 [M+H]⁺.

Step 2:

An oven-dried vial was equipped with a magnetic stir bar and charged with 1-(4-bromo-3-(methoxymethoxy)phenyl)-4-methyl-1H-imidazole (0.19 g, 0.64 mmol), bis(pinacolato)diboron (0.25 g, 0.98 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dicholoropalladium(II) (0.06 g, 0.07 mmol), and potassium acetate (0.19 g, 1.94 mmol) and was purged with argon. Dioxane (5 mL) was added, and the reaction was stirred at 90° C. for 2 h. The crude mixture was purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0-10% MeOH) to afford 1-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methyl-1H-imidazole (0.11 g, 0.32 mmol, 50%). MS m/z 345.2 [M+H]⁺.

Using the procedure described, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Structure Data

MS m/z 349.4 [M + H]⁺

Preparation of Starting Material: 3-[2,3-Dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-pyrazole

Step 1:

A 25 mL round bottom flask was charged with 1,4-diiodo-2,3-dimethoxybenzene (460 mg, 1.17 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (180 mg, 0.87 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (80 mg, 0.10 mmol) potassium carbonate (360 mg, 2.60 mmol), water (9.4 mL) and 1,4-dioxane (9.4 mL) and the reaction mixture was purged with N₂ for 15 minutes. The mixture was then heated at 80° C. for 2 hours. The reaction was cooled, concentrated and purified by silica gel chromatography eluting with a gradient of EtOAc/hexanes (30-100% EtOAc) to give 3-(4-iodo-2,3-dimethoxy-phenyl)-1-methyl-pyrazole (104 mg, 35% yield). MS m/z 345.0 [M+H]⁺.

Step 2:

A screw-cap tube was charged with 3-(4-iodo-2,3-dimethoxy-phenyl)-1-methyl-pyrazole (48 mg, 0.14 mmol), bis(pinacolato)diboron (0.04 ml, 0.30 mmol), triethylamine (0.05 ml, 0.40 mmol) and 1,4-dioxane (0.3 ml) and the headspace was purged with N₂ gas for 30 minutes. Then palladium(II) acetate (1.80 mg, 0.008 mmol) and 2-(dicyclohexylphosphino)biphenyl (5.2 mg, 0.02 mmol) were added and the reaction stirred at 80° C. for 1 h. The reaction was cooled, concentrated and purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (0-100% EtOAc) to give 3-[2,3-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-pyrazole (45 mg, 94% yield). MS m/z 345.2 [M+H]⁺.

Preparation of Starting Material: 4-[3,5-Dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2-yl-pyrazole

Step 1.

A round bottom flask was charged with 5-bromobenzene-1,3-diol (600 mg, 3.02 mmol) 1-(tetrahydro-2h-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole (1.4 g, 4.8 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (220 mg, 0.302 mmol), potassium carbonate (1.3 g, 9.4 mmol), 1,4-dioxane (36 mL) and water (36 mL) and the reaction was purged with N₂ for 15 minutes. The mixture was stirred at 80° C. for 1 hour. The reaction was cooled, concentrated and purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 30% MeOH), to give 5-(1-tetrahydropyran-2-ylpyrazol-4-yl)benzene-1,3-diol (600 mg, 77% yield). MS m/z 261.1 [M+H]⁺.

Step 2.

A solution of 5-(1-tetrahydropyran-2-ylpyrazol-4-yl)benzene-1,3-diol (600 mg, 2.31 mmol) in acetonitrile (4 mL) was cooled to 0° C. N-Iodosuccinimide (520 mg, 2.31 mmol) was added and the reaction was stirred at 0° C. for 5 minutes. The reaction was quenched with aqueous saturated sodium thiosulfate and extracted with dichloromethane. The organic layer was dried, concentrated and purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 30% MeOH) to give 2-iodo-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)benzene-1,3-diol (800 mg, 90% yield). MS m/z 387.1 [M+H]⁺.

Step 3.

A round bottom flask was charged with 2-iodo-5-(1-tetrahydropyran-2-ylpyrazol-4-yl)benzene-1,3-diol (400 mg, 1.04 mmol), iodomethane (0.14 mL, 2.2 mmol), potassium carbonate (310 mg, 2.24 mmol) and acetone (3.3 mL) and the mixture was heated at 50° C. for 12 hours. The reaction was cooled, concentrated and purified by silica gel chromatography eluting with a gradient of EtOAc/hexanes (30-100% EtOAc) to give 4-(4-iodo-3,5-dimethoxy-phenyl)-1-tetrahydropyran-2-yl-pyrazole (300 mg, 0.72 mmol, 70% yield). MS m/z 415.1 [M+H]⁺.

Step 4.

A round bottom flask was charged with 4-(4-iodo-3,5-dimethoxy-phenyl)-1-tetrahydropyran-2-yl-pyrazole (50 mg, 0.12 mmol), bis(pinacolato)diboron (0.04 ml, 0.3 mmol), triethylamine (0.05 ml, 0.4 mmol), and 1,4-dioxane (0.3 ml) and the reaction was purged with N₂ for 15 minutes. Then 1,4-dioxane (0.3 mL) and 2-(dicyclohexylphosphino)biphenyl (4.5 mg, 0.013 mmol) was dissolved in 1,4-dioxane (0.3 mL) was added and the reaction was heated at 90° C. for 12 hours. The mixture was cooled, concentrated and purified by silica gel chromatography eluting with a gradient of EtOAc/hexanes (0-100% EtOAc) to give 4-[3,5-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2-yl-pyrazole (50 mg, 99% yield). MS m/z 415.4 [M+H]⁺.

Preparation of Starting Material: 2-[4-Chloro-3-fluoro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1:

6-Bromo-3-chloro-2-fluoro-phenol (900 mg, 4.0 mmol) was dissolved in DMF (4.5 mL) at 0° C. Sodium tert-pentoxide (2.5 M in THF, 2 mL, 5.0 mmol) was added dropwise, followed by dropwise addition of chloromethyl methyl ether (405 μL, 5.34 mmol) and the reaction was stirred overnight at room temperature. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water, and then brine. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (30-100% EtOAc) to yield 1-bromo-4-chloro-3-fluoro-2-(methoxymethoxy)benzene (1.01 g, 94% yield) as a clear oil.

¹H NMR (acetone-d₆) δ: 7.50 (d, J=9 Hz, 1H), 7.28 (t, J=8 Hz, 1H), 5.26 (s, 2H), 3.62 (s, 3H).

Step 2:

A mixture of dry KOAc (1.5 g, 15 mmol), bis(pinacolato)diboron (1.02 g, 4.02 mmol), Pd(dppf)Cl₂—CH₂Cl₂ (90 mg, 0.108 mmol), and a solution of 1-bromo-4-chloro-3-fluoro-2-(methoxymethoxy)benzene (900 mg, 3.3 mmol) in toluene (12 mL) was purged with argon for 15 min. The mixture was heated at 110° C. for 16 h. Upon completion, the reaction was diluted with EtOAc and was filtered through celite. The filtrate was concentrated and purified by silica chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 5% MeOH) to yield 2-[4-chloro-3-fluoro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (524 mg, 47% yield) as a light orange oil.

¹H NMR (acetone-d₆) δ: 7.49 (d, J=8 Hz, 1H), 7.29 (t, J=7 Hz, 1H), 5.16 (s, 2H), 3.58 (s, 3H), 1.37 (s, 12H).

Preparation of Starting Material: 6-Chloro-8-methyl-imidazo[1,2-b]pyridazine

Step 1

A mixture of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (232 mg, 1.0 mmol), 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (142 mg, 1.0 mmol), Pd(dppf)Cl₂ (150 mg, 0.20 mmol), and K₂CO₃ (285 mg, 2.1 mmol), in dioxane (5 mL) and water (1 mL) was purged with argon for 15 min and heated to 90° C. for 16 h. The reaction was diluted with water (50 mL), and then extracted with CH₂Cl₂ (3×30 mL). The organic layers were washed with brine (2×20 mL), dried over Na₂SO₄, and then filtered and concentrated. The residue was purified by silica gel column chromatography eluting with a MeOH/CH₂Cl₂ gradient (5 to 10% MeOH) to afford 6-chloro-8-methyl-imidazo[1,2-b]pyridazine (85 mg, 50% yield). MS m/z 168.0, 170.0 [M+H]⁺.

Preparation of Starting Material: 6-Chloro-8-methyl-imidazo[1,2-b]pyridazine and tert-Butyl ((6-chloroimidazo[1,2-b]pyridazin-8-yl)methyl)carbamate

Step 1

A solution of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (232 mg, 1.0 mmol), dicyanozinc (150 mg, 1.2 mmol), and Pd(PPh₃)₄ (240 mg, 0.2 mmol) in dry DMF (4 mL) was heated in a microwave for 45 min at 100° C. The reaction was concentrated and purified by preparatory HPLC to afford 6-chloro-8-methyl-imidazo[1,2-b]pyridazine (85 mg, 50% yield). MS m/z 178.9, 181.1 [M+H]⁺.

Step 2

A solution of 6-chloro-8-methyl-imidazo[1,2-b]pyridazine (80 mg, 0.45 mmol), di-tert-butyl dicarbonate (147 mg, 0.67 mmol), and Ni (16 mg) in THE (5 mL) was stirred at room temperature for 16 h. The reaction was filtered and concentrated. The residue was purified by preparatory HPLC (10% MeOH in CH₂Cl₂), to afford tert-butyl ((6-chloroimidazo[1,2-b]pyridazin-8-yl)methyl)carbamate (36 mg, 28% yield). MS m/z 282.9, 284.8 [M+H]⁺.

Preparation of Starting Material: 6-Chloro-8-methoxy-imidazo[1,2-b]pyridazine

Step 1

A solution of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (234 mg, 1.0 mmol) and sodium methoxide (108 mg, 1.2 mmol) in methanol (4 mL) was heated to reflux for 12 h. The reaction was cooled to room temperature, concentrated, and then the residue was purified by preparatory HPLC to afford 6-chloro-8-methoxy-imidazo[1,2-b]pyridazine (100 mg, 54% yield). MS m/z 184.0, 186.0 [M+H]⁺.

Preparation of Starting Material: 5-Bromo-7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

Step 1

To a solution of 4-bromo-2-fluoro-6-nitroaniline (600 mg, 2.6 mmol) in tetrahydrofuran (5 mL), ethanol (5 mL), and water (1 mL) was added iron (1.5 g, 27 mmol), and ammonium chloride (1.5 g, 28 mmol). The mixture was heated to reflux for 16 hours, then cooled to room temperature, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 10% MeOH) to yield 5-bromo-3-fluorobenzene-1,2-diamine as a brown solid (400 mg, 76%). MS m/z 204.8, 206.8 [M+H]⁺.

Step 2:

A mixture of 5-bromo-3-fluorobenzene-1,2-diamine (400 mg, 2.0 mmol) and formic acid (5 mL) was stirred at 120° C. for 16 hours. After cooling, the solvent was removed and the residue was partitioned between EtOAc (200 mL) and sat. aq. NaHCO₃ (50 mL). The organic phase was dried over Na₂SO₄ and concentrated to afford crude 5-bromo-7-fluoro-1H-benzoimidazole as an off white solid (400 mg, 95%). MS m/z 215.0, 217.0 [M+H]⁺.

Step 3

A solution of 5-bromo-7-fluoro-1H-benzimidazole (200 mg, 0.93 mmol) in tetrahydrofuran (5 mL) was cooled to 0° C. and sodium hydride (15 mg, 0.60 mmol) was added. The reaction was stirred at 0° C. for 20 minutes, then 2-(trimethylsilyl)ethoxymethyl chloride (0.08 g, 0.48 mmol) was added. The mixture was stirred at room temperature for 2 h. The reaction was quenched with ice water, and the aqueous phase was extracted with EtOAc. The organic phase was dried over Na₂SO₄, concentrated and the residue was purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 10% MeOH) to afford 5-bromo-7-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (210 mg, 65%). MS m/z 345.0, 347.0 [M+H]⁺.

Preparation of Starting Material: 5-Bromo-6,7-difluoro-1-methyl-benzimidazole

Step 1

To a solution of 1,2,3-trifluoro-4-nitro-benzene (1.00 g, 5.65 mmol) and methylamine hydrochloride (409 mg, 5.94 mmol) in acetronitrile (10.0 mL) was added DIPEA (3.66 g, 28.2 mmol). The mixture was stirred for 3 hours at 70° C., then cooled to room temperature. The mixture was concentrated and the residue was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (0-5% EtOAc) to afford 2,3-difluoro-N-methyl-6-nitro-aniline (1.06 g, 99% yield) as a yellow solid. MS m/z 189.0 [M+H]⁺.

Step 2

To a solution of 2,3-difluoro-N-methyl-6-nitro-aniline (1.48 g, 7.87 mmol) in DMF (50.0 mL) was added NBS (1.79 g, 9.86 mmol). The mixture was stirred for 1 hour at 90° C., and then cooled to room temperature and quenched with brine (200 mL). The mixture was extracted with EtOAc (3×50 mL). The organic layers were dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (0-5% EtOAc) to afford 4-bromo-2,3-difluoro-N-methyl-6-nitro-aniline (1.75 g, 83% yield) as a yellow solid. MS m/z 267.0, 269.0 [M+H]⁺.

Step 3

A solution of 4-bromo-2,3-difluoro-N-methyl-6-nitro-aniline (1.85 g, 6.93 mmol) in tetrahydrofuran (50.0 mL) and methanol (50.0 mL) was cooled to 0° C. Then, Raney-nickel (500 mg) was added, followed by dropwise addition of hydrazine (227 mg, 6.94 mmol). The mixture was stirred for 15 min at 0° C. and filtered. The filtrate was concentrated to give crude 4-bromo-5,6-difluoro-Ni-methylbenzene-1,2-diamine (1.58 g, 96% yield) as a pale brown oil. MS m/z 237.0, 239.0 [M+H]⁺.

Step 4:

5-Bromo-3,4-difluoro-N2-methyl-benzene-1,2-diamine (1.58 g, 6.67 mmol) was suspended in formic acid (5 mL) and trimethyl orthoformate (5.0 mL, 46 mmol) was then added. The mixture was heated at reflux for 1 hour under a nitrogen atmosphere, and then cooled to room temperature. The mixture was concentrated and the residue was neutralized with sat. aq. NaHCO₃ to pH 8. The mixture was extracted with EtOAc (3×50 mL) and the organic layers were dried over Na₂SO₄, concentrated and purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (0-65% EtOAc) to afford 5-bromo-6,7-difluoro-1-methyl-benzimidazole (1.52 g, 92% yield) as a pale brown solid. MS m/z 247.0, 249.0 [M+H]⁺.

Preparation of Starting Material: Racemic (3S,4S)-3-fluoro-2,2,6,6-tetramethyl-piperidin-4-amine

Step 1

To an oven-dried three-necked flask was added 2,2,6,6-tetramethylpiperidin-4-one (20.0 g, 129 mmol). After evacuating and back-filling with nitrogen 3 times, tetrahydrofuran (90 mL) was added under nitrogen. The solution was cooled to −78° C., and then lithium bis(trimethysilyl)amide in tetrahydrofuran (193 mL, 193 mmol, 1 mol/L) was added dropwise. Following complete reaction, the mixture was stirred at −78° C. for 30 min. N-fluorobenzensulfonimide (42.6 g, 135 mol) was added potion wise as a solid over 20 min under nitrogen. The reaction was then gradually warmed to room temperature, and the mixture was further stirred at room temperature for 16 hours. The reaction was filtered to remove solid, and then the mixture was concentrated, and purified by flash chromatography using EtOAc and petroleum ether (0-10% EtOAc) as eluent to afford 3-fluoro-2,2,6,6-tetramethylpiperidin-4-one as a pale yellow solid (10.0 g, 45.5%). MS m/z: 174.1 [M+H]⁺.

Step 2:

3-Fluoro-2,2,6,6-tetramethylpiperidin-4-one (7.2 g, 41.6 mmol) and (4-methoxyphenyl)methanamine (6.3 g, 45.8 mmol) were dissolved in methanol (40 mL). Acetic acid (6 mL, 104 mmol) was then added. The resulting mixture was stirred at room temperature for 1 h, then NaBH₃CN (3.9 g, 62.4 mmol) was added, and the mixture was stirred for an additional 16 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (10-30% EtOAc) to afford C-cis racemic (3S,4S)-3-fluoro-N-[(4-methoxyphenyl)methyl]-2,2,6,6-tetramethyl-piperidin-4-amine (5.0 g, 40.0%) and C-trans racemic (3S,4R)-3-fluoro-N-(4-methoxybenzyl)-2,2,6,6-tetramethylpiperidin-4-amine (2.7 g, 22.0%).

C-cis racemic (3S,4S)-3-fluoro-N-[(4-methoxyphenyl)methyl]-2,2,6,6-tetramethyl-piperidin-4-amine: MS m/z: 295.2 [M+H]⁺; ¹H NMR (DMSO-d₆) δ 7.23 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 3.95 (dd, J₁=9.6 Hz, J₂=51.2 Hz, 1H), 3.73-3.63 (m, 5H), 3.33 (br s, 1H), 3.03-2.97 (m, 1H), 1.87-1.83 (m, 2H), 1.65 (br, 1H), 1.09-1.04 (m, 12H).

C-trans racemic: (3S,4R)-3-fluoro-N-(4-methoxybenzyl)-2,2,6,6-tetramethylpiperidin-4-amine: MS m/z: 295.2 [M+H]⁺; ¹H NMR (DMSO-d₆) δ 7.25 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.33 (d, J=50.8 Hz, 1H), 3.72 (s, 5H), 3.33 (br s, 2H), 2.95 (dd, J₁=15.6 Hz, J₂=28.4 Hz, 1H), 1.53 (dd, J₁=4.0 Hz, J₂=8.8 Hz, 1H), 1.21-1.03 (m, 13H).

Step 3

To a three-neck round bottom flask charged with a thermometer, pressure drop funnel and hydrogen balloon was added racemic (3S,4S)-3-fluoro-N-[(4-methoxyphenyl)methyl]-2,2,6,6-tetramethyl-piperidin-4-amine (10.0 g, 33.97 mmol), MeOH (150 mL), palladium on carbon (10 wt %) (3.0 g, 2.8 mmol), and formic acid (0.20 g, 4.0 mmol). The flask was evacuated and backfilled with hydrogen twice. The mixture was stirred at 45° C. for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with a gradient of MeOH/CH₂Cl₂ (0 to 100% MeOH) to yield racemic (3S,4S)-3-fluoro-2,2,6,6-tetramethyl-piperidin-4-amine (4.8 g, 81%). MS m/z 175.2 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 4.91 (d, J=48 Hz, 1H), 4.25 (dd, J₁=11.6 Hz, J₂=30 Hz, 1H), 2.14-2.00 (m, 2H).1.62-1.57 (m, 12H); 3NHs not observed.

Preparation of Starting Material: (3S,4S)-3-Fluoro-2,2,6,6-tetramethylpiperidin-4-amine

Step 1

Racemic (3S,4S)-3-fluoro-N-[(4-methoxyphenyl)methyl]-2,2,6,6-tetramethyl-piperidin-4-amine (5.0 g, 12.7 mmol) was dissolved in methanol (80 mL), then di-tert-butyl dicarbonate (4.1 g, 19.5 mmol) and triethyl amine (2.7 mmol, 19.5 mmol) were added sequentially. The resultant mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure, the residue was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (0-50% EtOAc) to afford the desired tert-butyl ((3 S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)(4-methoxybenzyl)carbamate (4.1 g, 61.0%) as a colorless oil. MS m/z: 395.2 [M+H]⁺.

Step 2:

A total of 5 g of racemic tert-butyl ((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)(4-methoxybenzyl)carbamate were separated by chiral-Prep-HPLC (SFC-200, Thar, Waters) using a WHELK 50*250 mm, 10 um (Daicel) column with CO₂/IPA(0.2% Methanol Ammonia)=90/10 as the mobile phase to afford tert-butyl ((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)(4-methoxybenzyl)carbamate (2.2 g, 44% yield) and tert-butyl ((3R,4R)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)(4-methoxybenzyl)carbamate (1.8 g, 36%).

Step 3

tert-Butyl ((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)(4-methoxybenzyl) carbamate (2.2 g, 5.6 mmol) was dissolved in acetonitrile (40 mL), ammonium cerium(IV) nitrate (9.2 g, 16.8 mmol) was added, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and purified by silica gel chromatography eluting with a gradient of EtOAc/hexanes (0-80% EtOAc) to afford crude tert-butyl ((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)carbamate (1.5 g, 98% yield), which was used to the next step without further purification. MS m/z: 275.2 [M+H]⁺.

Step 4:The crude tert-butyl ((3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-yl)carbamate (1.5 g, 0.54 mmol) obtained in step 3 was dissolved in CH₂Cl₂ (20 mL), and then 2 mL of HCl in dioxane (4 mol/L) was added, and the mixture was stirred at room temperature for 16 h. The precipitate was filtered, washed with 5 mL of CH₂Cl₂ and dried to yield (3S,4S)-3-fluoro-2,2,6,6-tetramethylpiperidin-4-amine (533 mg, HCl salt, 47% yield) as a white solid.

MS m/z: 175.2 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 4.91 (d, J=48 Hz, 1H), 4.25 (dd, J=11.6 Hz, 30 Hz, 1H), 2.14-2.00 (m, 2H).1.62-1.57 (m, 12H); 3NHs not observed.

Using the procedure described, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Structure Data

MS m/z 175.2 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 4.90 (d, J = 48 Hz, 1H), 4.25 (dd, J₁ = 10.8 Hz, J₂ = 28.8 Hz, 1H), 2.14-2.00 (m, 2H). 1.64-1.50 (m, 12H), 3 NHs not observed.

Preparation of Starting Material: Racemic (3R,4R)-4-amino-2,2,6,6-tetramethyl-piperidin-3-ol dihydrochloride

Step 1:

2,2,6,6-Tetramethylpiperidine-3,4-dione (2.98 g, 17.6 mmol) was dissolved in ethanol (15 mL), followed by the addition of aqueous hydroxylamine (1.2 mL, 20 mmol, 50 wt % in H₂O). The reaction was sealed and heated to 70° C. for 10 minutes, and then cooled to room temperature and concentrated providing crude (E)-4-(hydroxyimino)-2,2,6,6-tetramethylpiperidin-3-one (2.1 g, 63% yield) which was used directly in the next step. MS m/z 185.3 [M+H]⁺.

Step 2:

(E)-4-(hydroxyimino)-2,2,6,6-tetramethylpiperidin-3-one (2.1 g, 11 mmol), zinc (4.5 g, 69 mmol), and aqueous sodium hydroxide (16 mL, 6.0 M) were combined and heated at 70° C. for 30 min and then cooled to room temperature. The reaction was filtered through a frit, rinsing with CH₂Cl₂/MeOH. The aqueous layer was extracted twice with CH₂Cl₂/MeOH (9:1) and three times with CHCl₃/iPrOH (7:3). The combined organic layers were dried over sodium sulfate, filtered and then concentrated to yield crude 4-amino-2,2,6,6-tetramethyl-piperidin-3-one (1.75 g, 90%) as an orange oil which was used directly in the next step without purification.

Step 3:

4-Amino-2,2,6,6-tetramethyl-piperidin-3-one (1.75 g, 10.3 mmol), DMF (6 mL), and N,N-diisopropylethylamine (2.70 mL, 15.5 mmol) were stirred at room temperature and then cooled to 0° C. Benzyl chloroformate (2.20 mL, 15.5 mmol) was added dropwise. Stirring was continued at 0° C. for 25 min. The reaction was then partitioned between EtOAc and brine and the layers were separated. The aqueous layer was extracted twice with EtOAc and the combined organic layers were washed three times with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with a EtOAc/hexanes gradient (0-100% EtOAc) to yield benzyl N-(2,2,6,6-tetramethyl-3-oxo-4-piperidyl)carbamate (1.45 g, 46%) as an orange solid.

MS m/z 305.6 [M+H]⁺; ¹H NMR (DMSO-d₆) δ: 7.55 (br d, J=8.5 Hz, 1H), 7.29-7.41 (m, 5H), 5.06 (s, 2H), 4.86-4.96 (m, 1H), 4.69 (s, 1H), 2.13 (dd, J=12.8, 8.9 Hz, 1H), 1.58 (dd, J=12.8, 7.3 Hz, 1H), 1.28 (d, J=1.8 Hz, 6H), 1.24 (s, 3H), 1.09 (s, 3H).

Step 4

Benzyl N-(2,2,6,6-tetramethyl-3-oxo-4-piperidyl)carbamate (1.20 g, 3.95 mmol) was dissolved in MeOH (5 mL), followed by the addition of sodium borohydride (247 mg, 6.54 mmol). The reaction was stirred at room temperature for 1 h, then acetone (3 mL) was added slowly and the reaction was concentrated. The residue was partitioned between EtOAc and H₂O and the layers were separated. The aqueous layer was extracted four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated to yield crude racemic benzyl N-[(3R,4R)-3-hydroxy-2,2,6,6-tetramethyl-4-piperidyl]carbamate that was used directly in the next step.

MS m/z 307.5 [M+H]⁺; ¹H NMR (DMSO-d₆) δ 7.30-7.40 (m, 6H), 5.01 (d, J=5.8 Hz, 2H), 4.94-4.95 (m, 1H), 3.91-4.00 (m, 1H), 2.93 (br d, J=7.3 Hz, 1H), 1.76 (dd, J=12.2, 9.8 Hz, 1H), 1.46 (br dd, J=12.8, 5.5 Hz, 1H), 1.14 (s, 3H), 1.08 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H); 1H not observed (NH).

Step 5

The residue from Step 4 containing racemic benzyl N-[(3R,4R)-3-hydroxy-2,2,6,6-tetramethyl-4-piperidyl]carbamate was dissolved in methanol (5 mL), followed by the addition of 10% palladium on carbon (293 mg, 0.275 mmol). The reaction was stirred at room temperature while hydrogen gas was used to sparge the solution for 3 minutes. Stirring was continued under a hydrogen atmosphere at room temperature for 72 h. The reaction was filtered through celite and rinsed with methanol. Methanolic HCl (5 mL, 1.25 M) was added to the filtrate and the filtrate was concentrated to yield racemic (3R,4R)-4-amino-2,2,6,6-tetramethyl-piperidin-3-ol dihydrochloride (251 mg, 26% yield).

MS m/z 173.0 [M+H]⁺; ¹H NMR (1:1 chloroform-d: methanol-d₄) δ: 3.48 (q, J=7.6 Hz, 1H), 2.86 (d, J=7.6 Hz, 1H), 2.00 (dd, J=12.8, 8.5 Hz, 1H), 1.57 (dd, J=12.8, 7.3 Hz, 1H), 1.30 (d, J=2.1 Hz, 6H), 1.23 (s, 3H), 1.23 (s, 3H); 4Hs not observed (3NHs and OH).

Preparation of Starting Material: Racemic (3aR,4R,6aS)-N,N-dimethyl-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-4-amine

Step 1

Racemic tert-butyl 4-oxo-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (523.8 mg, 2.325 mmol), dichloromethane (5 mL), aqueous dimethylamine (2.0 mL, 40 wt. %, 6.8 equiv), and sodium triacetoxyborohydride (2.06 g, 9.72 mmol, 4.18 equiv) were combined and stirred at room temperature for 20 h. The reaction was partitioned between CH₂Cl₂ and aqueous sodium hydroxide (1.0 M) and the layers were separated. The aqueous layer was extracted twice with CH₂Cl₂/MeOH (9:1) and once with CHCl₃/iPrOH (7:3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with a gradient of MeOH/CH₂Cl₂ (0-30% MeOH/NH₄OH, 2.5% NH₄OH v/v) to yield racemic tert-butyl (3aR,4R,6aS)-4-(dimethylamino)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (452.4 mg, 76% yield).

MS m/z 255.3 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 3.42-3.51 (m, 1H), 3.39 (dd, J=8.7, 4.1 Hz, 2H), 3.20 (br d, J=10.4 Hz, 1H), 2.80 (br s, 1H), 2.62-2.73 (m, 1H), 2.42-2.51 (m, 1H), 2.22 (s, 6H), 1.91-2.01 (m, 1H), 1.83-1.90 (m, 1H), 1.57 (quin, J=10.6 Hz, 1H), 1.45-1.50 (m, 1H), 1.43 (s, 9H).

Step 2

Racemic tert-butyl (3aR,4R,6aS)-4-(dimethylamino)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (43.1 mg, 0.169 mmol) was dissolved in TFA (2 mL) and stirred at room temperature for 4 h. The reaction was concentrated and the residue used directly in subsequent reactions, assuming a quantitative yield of racemic (3aR,4R,6aS)-N,N-dimethyl-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-4-amine 2,2,2-trifluoroacetic acid. MS m/z 155.3 [M+H]⁺.

Preparation of Starting Material: N-(tert-Butyl)pyrrolidin-3-amine

Step 1

A dry vial was charged with 1-benzylpyrrolidin-3-one (4.0 g, 22.8 mmol), 2-methylpropan-2-amine (3.8 g, 52.0 mmol) and Ti(OiPr)₄ (6.0 mL, 20.2 mmol). The mixture was purged with N₂ for 15 min and then allowed to stir at room temperature for 2 h. The resulting (E)-1-benzyl-N-(tert-butyl)pyrrolidin-3-imine was used without further purification.

Step 2:

To the mixture from step 1 was added dry methanol (40 mL) and the reaction was cooled to 0° C. in an ice bath. NaBH₄ (1.6 g, 42.3 mmol) was added slowly in portions (caution: very exothermic reaction). Once evolution of the gas subsided, the mixture was warmed to room temperature and stirred for 2h at room temperature. Upon completion, 0.1M NaOH solution (20 mL) was added to precipitate the titanium salts. The biphasic mixture was filtered through celite and washed with methanol. The solvent was removed under vacuum and the crude oil was purified by reverse phase chromatography using a acetonitrile/H₂O gradient (10%-100% acetonitrile) to afford 1-benzyl-N-(tert-butyl)pyrrolidine-3-amine (3.2 g, 60% yield) as a colorless oil.

Step 3

To an oven-dry round bottom flask containing palladium hydroxide on activated carbon (320 mg) was added 1-benzyl-N-(tert-butyl)pyrrolidine-3-amine (3.2 g, 13.8 mmol) dissolved in MeOH (20 mL). The mixture was sparged with H₂ for 5 minutes and a balloon of H₂ was placed on top of the flask and the reaction was stirred for 2 h at room temperature. The reaction mixture was filtered through celite, washed with MeOH and concentrated to afford N-(tert-butyl)pyrrolidin-3-amine (1.89 g, 96% yield) as a colorless oil which solidified upon standing.

¹H NMR (methanol-d₄) δ: 4.21 (dq, J=14.4, 7.0 Hz, 1H), 3.80 (dd, J=12.7, 8.0 Hz, 1H), 3.58-3.50 (m, 2H), 3.38-3.32 (m, 1H), 2.62-2.56 (m, 1H), 2.28-2.20 (m, 1H), 1.42 (s, 9H); 2NHs not observed.

Using the procedure described, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Structure Data

¹H NMR (chloroform-d) δ: 0.93 (d, J = 6.71 Hz, 6H) 1.74 (dq, J = 13.28, 6.66 Hz, 2H) 1.98-2.15 (m, 1H) 2.42 (d, J = 6.71 Hz, 2H) 2.98 (dd, J = 11.60, 3.66 Hz, 1H) 3.06-3.21 (m, 2H) 3.29 (dt, J = 11.14, 7.40 Hz, 1H) 3.35-3.46 (m, 3H)

¹H NMR (chloroform-d) δ: 1.57 (br d, J = 5.49 Hz, 1H) 2.02 (br dd, J = 13.12, 6.71 Hz, 1H) 2.38 (br s, 2H) 2.70-2.86 (m, 3H) 2.92 (br d, J = 8.09 Hz, 1H) 3.00 (br dd, J = 11.14, 5.80 Hz, 1H) 3.07- 3.16 (m, 1H) 3.31 (br s, 1H) 3.49 (s, 1H) 3.67 (br t, J = 4.73 Hz, 2H)

MS m/z 155 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 3.35-3.41 (m, 1H), 3.03-3.16 (m, 3H), 2.86-2.97 (m, 1H), 2.67-2.75 (m, 1H), 2.03-2.15 (m, 1H), 1.88-2.00 (m, 2H), 1.68-1.79 (m, 2H), 1.54-1.68 (m, 3H), 1.30-1.44 (m, 2H); 2NHs not observed

MS m/z 159.2 [M + H]⁺

MS m/z 173.3 [M + H]⁺; ¹H NMR (chloroform-d) δ: 3.46-3.39 (m, 1H), 3.36 (s, 3H), 3.27-3.17 (m, 3H), 3.09-3.01 (m, 2H), 2.75-2.65 (m, 1H), 2.18-2.07 (m, 1H), 1.65-1.53 (m, 1H), 1.65- 1.53 (m, 1H), 1.08 (s, 3H), 1.07 (s, 3H); 1NH not observed

¹H NMR (chloroform-d) δ: 4.45-4.20 (m, 2H), 3.81-3.68 (m, 1H), 3.31-3.15 (m, 2H), 3.12- 2.88 (m, 3H), 2.40-2.23 (m, 1H), 1.95-1.80 (m, 1H), 1.12 (t, J = 7.9 Hz, 3H); 2NHs not observed

¹H NMR (chloroform-d) δ: 4.57-4.44 (m, 2H), 4.43-4.28 (m, 2H), 3.54-3.41 (m, 1H), 2.81- 2.64 (m, 2H), 2.62-2.50 (m, 1H), 2.34-2.13 (m, 2H), 1.60-1.41 (m, 4H); 2NHs not observed

MS m/z 143.3 [M + H]⁺

¹H NMR (methanol-d₄) δ: 1.87-2.03 (m, 2H) 2.12-2.31 (m, 3H) 2.32-2.45 (m, 2H) 2.47- 2.59 (m, 1H) 3.38-3.49 (m, 2H) 3.56 (br dd, J = 12.21, 6.41 Hz, 1H) 3.73 (br dd, J = 12.21, 8.24 Hz, 1H) 3.83-3.92 (m, 1H) 3.94-4.06 (m, 1H); 2NHs not observed

¹H NMR (methanol-d₄) δ: 1.87-2.03 (m, 2H) 2.14-2.31 (m, 3H) 2.38 (br d, J = 3.66 Hz, 2H) 2.52 (br dd, J = 14.04, 7.02 Hz, 1H) 3.36-3.51 (m, 2H) 3.53-3.64 (m, 1H) 3.73 (br dd, J = 12.66, 8.09 Hz, 1H) 3.88 (br t, J = 8.09 Hz, 1H) 3.94- 4.06 (m, 1H); 2NHs not observed

MS m/z 141.1 [M + H]⁺

MS m/z 185.3 [M + H]⁺

Preparation of Starting Material: N-(Pyrrolidin-3-ylmethyl)propan-2-amine hydrochloride

Step 1

To a round bottom flask were added 1-Boc-3-formylpyrrolidine (300 mg, 1.5 mmol), isopropyl amine (0.2 mL, 2.54 mmol) and methylene chloride (5 mL). The mixture was stirred for 30 min at room temperature followed by the portion-wise addition of sodium triacetoxyborohydride (636 mg, 3 mmol) and the mixture continued to stir for 16 h at room temperature. The reaction was quenched by the addition of 1.0 M NaOH and washed with water. The aqueous phase was extracted with CH₂Cl₂ (2 times) and the combined organic layers were dried over Mg₂SO₄. The solvent volume was reduced in vacuo and an HCl solution (2.0M in ether, 2 mL) was added. The mixture was stirred for 5 h at room temperature, and the solids were collected by filtration, and dried to provide N-(pyrrolidin-3-ylmethyl)propan-2-amine bishydrochloride salt (160 mg, 50% yield) as an off white solid.

¹H NMR (DMSO-d₆) δ: 9.70-9.45 (m, 2H), 9.19 (br s, 2H), 3.39-3.30 (m, 1H), 3.25 (dd, J=6.1, 11.9 Hz, 2H), 3.17-3.07 (m, 1H), 3.06-2.94 (m, 3H), 2.75-2.64 (m, 1H), 2.20-2.06 (m, 1H), 1.81-1.66 (m, 1H), 1.27 (d, J=6.3 Hz, 6H).

Using the procedure described, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from: Structure Data

Structure Data

¹H NMR (methanol-d₄) δ: 3.66-3.55 (m, 1H), 3.53-3.43 (m, 1H), 3.38-3.29 (m, 2H), 3.25- 3.13 (m, 2H), 3.13-3.02 (m, 1H), 2.77-2.63 (m, 1H), 2.42-2.30 (m, 1H), 1.92-1.77 (m, 1H), 1.41 (s, 9H); 1NH not observed.

¹H NMR (DMSO-d₆) δ: 9.25-8.98 (m, 2H), 8.96- 8.74 (m, 2H), 4.00-3.87 (m, 2H), 3.45-3.36 (m, 1H), 3.35-3.23 (m, 4H), 3.23-3.12 (m, 1H), 3.12-3.02 (m, 2H), 2.93 (br s, 1H), 2.64-2.53 (m, 1H), 2.20-2.07 (m, 1H), 1.99-1.87 (m, 2H), 1.74-1.62 (m, 1H), 1.62-1.50 (m, 2H)

¹H NMR (methanol-d₄) δ: 1.76-1.87 (m, 1H) 1.95 (br d, J = 9.77 Hz, 2H) 2.17-2.29 (m, 2H) 2.29-2.44 (br s, 3H) 2.64-2.79 (m, 1H) 2.99- 3.15 (m, 3H) 3.33 (br s, 1H) 3.46 (br d, J = 4.27 Hz, 1H) 3.53-3.65 (m, 1H) 3.80 (br t, J = 8.09 Hz, 1H); 2NHs not observed

Preparation of Starting Material: N-(Pyrrolidin-3-ylmethyl)tetrahydrofuran-3-amine

Step 1

To a solution of tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (50 mg, 0.25 mmol) and dihydrofuran-3(2H)-one (43 mg, 0.50 mmol) in CH₂Cl₂ (1.3 mL) was added sodium triacetoxyborohydride (110 mg, 0.050 mmol). The reaction was stirred at room temperature for 2 hours and then partitioned between EtOAc and aq. NaHCO₃. The organic phase was collected, and the aqueous layer was extracted once more with EtOAc. The organic phases were combined, washed with water, then brine, dried over Na₂SO₄ and then concentrated to afford tert-butyl 3-(((tetrahydrofuran-3-yl)amino)methyl)pyrrolidine-1-carboxylate which was used without further purification. MS m/z 271.4 [M+H]⁺.

Step 2:

3-(((Tetrahydrofuran-3-yl)amino)methyl)pyrrolidine-1-carboxylate from step 1 was dissolved in CH₂Cl₂ (2 mL) and then trifluoroacetic acid (0.5 mL) was added. The reaction was stirred at room temperature for 1 hour and then concentrated under high vacuum to afford N-(pyrrolidin-3-ylmethyl)tetrahydrofuran-3-amine which was used without further purification. MS m/z 171.3 [M+H]⁺.

Using the procedure described, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Structure Data

MS m/z 211.2 [M + H]⁺

Preparation of Starting Material (R)-N-(tert-Butyl)pyrrolidin-3-amine

Step 1

(R)-1-Benzylpyrrolidin-3-amine (2.0 g, 11.3 mmol), molecular sieves (2.0 g), and acetone (4.2 mL, 57.0 mmol) were mixed in a microwave vial and the mixture was heated in a microwave at 60° C. for 4 h. The molecular sieves were filtered off and the red solution was concentrated. The crude red oil was diluted with THE (4.0 mL) and 1.6 M solution of methyl lithium (8.7 mL, 14.0 mmol) was added slowly at room temperature. The reaction was stirred at room temperature for 4 h. The reaction mixture was then quenched with water and extracted with EtOAc, and the organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography using a MeOH/CH₂Cl₂ gradient (0-30%), followed by reverse phase purification using a gradient from 10% ACN/H₂O up to 100% ACN to afford (R)-1-benzyl-N-(tert-butyl)pyrrolidin-3-amine (0.2 g, 9% yield) as a colorless oil.

Step 2

To a round bottom flask containing Pd(OH)₂/C was added MeOH (10 mL) followed by (R)-1-benzyl-N-(tert-butyl)pyrrolidin-3-amine (0.2 g, 0.9 mmol) and the solvent was bubbled with H₂ for 5 min. A balloon containing H₂ was then placed on top of the flask and the reaction was allowed to stir for 2 h at room temperature. The solution was filtered over Celite and then concentrated to afford (R)-N-(tert-butyl)pyrrolidin-3-amine (0.12 g, 94% yield) as a colorless oil.

¹H NMR (methanol-d₄) δ: 4.23 (dq, J=14.0, 7.2 Hz, 1H), 3.83 (dd, J=12.5, 9.0 Hz, 1H), 3.62-3.50 (m, 2H), 3.40-3.33 (m, 1H), 2.66-2.58 (m, 1H), 2.30-2.23 (m, 1H), 1.46 (s, 9H).

Using the procedure described, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Structure Data

¹H NMR (methanol-d₄) δ: 4.23 (dq, J = 15.0, 8.0 Hz, 1H), 3.83 (dd, J = 12.9, 8.3 Hz, 1H), 3.62-3.52 (m, 2H), 3.40-3.33 (m, 1H), 2.65-2.59 (m, 1H), 2.26 (dq, J = 16.3, 8.4 Hz, 1H), 1.46 (s, 9H)

Example 1 Preparation of Compound 15

Step 1

A solution of 3-(methylthio)-1,2,4-triazine (500 mg, 3.9 mmol) in 10 mL of CH₂Cl₂ was cooled in an ice-water batch, and m-CPBA (958 mg, 3.9 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h until UPLC showed complete consumption of the starting material. The solvent was removed under reduced pressure without heating. The residue was redissolved in 5 mL of n-BuOH, N,2,2,6,6-pentamethylpiperidin-4-amine (1.0 g, 5.9 mmol) was added, and the reaction mixture was heated to 100° C. for 16 h. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. The crude product, N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine, was used as is in the next step.

Step 2:

N-Methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine prepared in step 1 was dissolved in 10 mL of MeOH and 5 mL of water. Bromine (200 μL, 3.9 mmol) was added, and the reaction mixture was stirred for 30 min at room temperature until UPLC showed full conversion. The solvents were removed under reduced pressure. The residue was dissolved in EtOAc (20 mL) and washed with water followed by brine. The organic layer was dried over Na₂SO₄, concentrated, and purified using silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 30% MeOH) to yield 6-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (367 mg, 29%) as brownish solid.

MS m/z 328.2, 330.3 [M+H]⁺; ¹H NMR (methanol-d₄) S: 8.46 (s, 1H), 5.15-5.32 (m, 1H), 3.10 (s, 3H), 2.04-2.09 (m, 2H), 1.96-1.99 (m, 2H), 1.58 (s, 6H), 1.54 (s, 6H), NH not observed.

Step 3:

An oven-dried flask was equipped with a magnetic stir bar and charged with 6-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (40 mg, 0.12 mmol), 4-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-tetrahydropyran-2-yl-pyrazole (61 mg, 0.15 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (9 mg, 0.012 mmol), and K₂CO₃ (51 mg, 0.37 mmol). The flask was sealed with a rubber septum and then evacuated and backfilled with argon. Dioxane (2 mL) and water (0.5 mL) were added, and the reaction was heated to 90° C. for 16 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 30% MeOH) to provide 6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (41 mg, 63%) as a brownish solid. MS m/z 536.5 [M+H]⁺.

Step 4:

To a solution of 6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (41 mg, 0.077 mmol) in CH₂Cl₂ (1 mL) and 2 drops of MeOH was added HCl (4 mol/L) in 1,4-dioxane (38 μL, 0.15 mmol). The reaction was stirred for 5 h until UPLC showed complete consumption of the starting material. The solvents were removed under reduced pressure, and the product was purified by column chromatography eluting with a gradient CH₂Cl₂/MeOH (5 to 3000 MeOH). Provided 2-[3-[methyl-(2,2,6,6-tetramethyl-4-piperidyl)amino]-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol; dihydrochloride (24 mg, 65H) as brownish solid.

MS m/z 48.5 [M+H]; ¹H NMR (methanol-d₄) δ: 9.11 (s, 1H), 8.03 (br. s., 2H), 7.84 (d, J=7.9 Hz, 1H), 7.25 (dd, J=8.2, 1.9 Hz, 1H), 7.21 (d, J=1.9 Hz, 1H), 5.32-5.46 (m, 1H), 3.23 (s, 3H), 1.93-2.10 (m, 3H), 1.65 (s, 6H), 1.54 (s, 6H); 3Hs not observed (2N1s and OH).

Using the procedure described for Example 1, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 10 MS m/z 422.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.78 (br s, 1H), 9.65 (s, 1H), 9.43 (s, br, 1H), 9.09 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.03 (s, 1H), 7.38-7.35 (m, 2H), 5.21- 5.29 (m, 1H), 3.13 (s, 3H), 2.38 (s, 3H), 2.09 (t, J = 12.0 Hz, 2H), 1.78 (d, J = 12.0 Hz, 2H), 1.52 (s, 6H), 1.51 (s, 6H) 50 MS m/z 426.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.64 (br s, 1H), 9.28 (br s, 1H), 9.10 (s, 1H), 8.22 (br s, 1H), 8.06 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.24 (s, 1H), 5.22 (t, J = 13.0 Hz, 1H), 3.11 (s, 3H), 1.94- 2.07 (m, 2H), 1.77 (d, J = 10.0 Hz, 2H), 1.49 (s, 6H), 1.46 (s, 6H); 1H is from HCl salt 87 MS m/z 406.5 [M + H]⁺. ¹H NMR (methanol-d₄) δ: 9.10 (s, 1H), 8.02 (s, 2H), 7.84, (d, J = 8.09 Hz, 1H), 7.24 (d, J = 8.00 Hz, 1H), 7.21 (s, 1H), 6.00-5.56 (m, 1H) 3.74 (s, 3H), 3.12 (s, 3H), 2.75-2.60 (m, 2H), 2.42-2.30 (m, 2H), 2.29-2.17 (m, 2H), 2.16-1.97 (m, 4H), 1.96-1.87 (m, 2H); 2NHs not observed (NH and OH) 105 MS m/z 393.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.13 (s, 1H), 8.77 (dd, J = 4.6, 1.5 Hz, 1H), 8.41 (s, 1H), 8.37 (d, J = 7.3 Hz, 1H), 7.47 (s, 1H), 7.40 (dd, J = 8.2, 4.6 Hz, 1H), 5.36-5.48 (m, 1H), 3.26 (s, 3H), 1.95-2.09 (m, 4H), 1.65 (s, 6H), 1.55 (s, 6H); 2Hs not observed (NH and OH) 125 MS m/z 426.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.11 (s, 1H), 7.66-7.83 (m, 2H), 7.50 (br s, 1H), 6.77 (t, J = 2.7 Hz, 1H), 5.32-5.45 (m, 1H), 3.23 (s, 3H), 1.92-2.01 (m, 4H), 1.62 (s, 6H), 1.51 (s, 6H); 3Hs not observed (2 NHs and OH)

Example 2 Preparation of Compound 1

Step 1

An oven-dried flask was equipped with a magnetic stir bar and charged with 6-bromo-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (80 mg, 0.24 mmol), 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-oxazole (92 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (28 mg, 0.024 mmol), and Na₂CO₃ (77.5 mg, 0.73 mmol). The flask was sealed with a rubber septum, and then evacuated and backfilled with argon. Dioxane (2 mL) and water (0.5 mL) were added, and the reaction was heated to 90° C. for 16 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 30% MeOH) to provide 6-(2-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (38 mg, 36%) as a brownish solid. MS m/z 437.5 [M+H]⁺.

Step 2:

6-[2-Methoxy-4-(5-methyloxazol-2-yl)phenyl]-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (38 mg, 0.09 mmol) in CH₂Cl₂ (2 mL) was treated with BBr₃ in CH₂Cl₂ (1 mol/L, 0.87 mL). The reaction was stirred at room temperature for 4 h until UPLC showed complete consumption of the starting material. The precipitate was filtered and dried to give 2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)-5-(5-methyloxazol-2-yl)phenol hydrobromide (13 mg, 35%) as an orange solid.

MS m/z 423.5 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 9.14 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.61 (dd, J=8.2, 1.6 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 6.96 (d, J=1.3 Hz, 1H), 5.37-5.45 (m, 1H), 3.25 (s, 3H), 2.46 (s, 3H), 1.98-2.05 (m, 4H), 1.66 (s, 6H), 1.55 (s, 6H); 2Hs not observed (NH and OH).

Using the procedure described for Example 2, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 17 MS m/z 408.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.33 (d, J = 2.1 Hz, 1H), 7.74-7.81 (m, 2H), 7.37-7.48 (m, 2H), 6.57 (s, 1H), 6.03 (s, 1H), 4.46-4.59 (m, 1H), 3.21 (s, 3H), 2.06-2.30 (m, 4H), 1.66 (s, 6H), 1.62 (s, 6H); 2Hs not observed (NH and OH). 368 MS m/z 438.5 [M + H]⁺. ¹H NMR (methanol-d₄): 9.11 (s, 1H), 7.71 (s, 1H), 7.40 (d, J = 8.00 Hz, 2H), 7.32 (d, J = 8.50 Hz, 2H), 7.31 (s, 1H), 6.80 (s, 1H), 5.51 (s, 3H), 5.36-5.39 (m, 1H), 4.01 (s, 3H), 1.96-2.05 (m, 4H), 1.66 (s, 6H), 1.54 (s, 6H) 376 MS m/z 410.5 [M + H]⁺. ¹H NMR (methanol-d₄): 8.89 (s, 1H), 8.06 (s, 2H), 6.85-6.91 (m, 2H), 4.31-4.26 (m, 1H), 4.25-4.17 (m, 1H), 4.02-3.96 (m, 1H), 3.93 (s, 3H), 3.81- 3.75 (m, 2H), 2.71-2.60 (m, 1H), 2.33-2.24 (m, 1H), 1.50 (s, 9H); 3Hs not observed (2NHs and OH)

Example 3 Preparation of Compound 16

Step 1:

An oven-dried flask was equipped with a magnetic stir bar and charged with 6-bromo-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (450 mg, 1.37 mmol), triisopropyl-[3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]silane (658 mg, 1.51 mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (102 mg, 0.14 mmol) and K₂CO₃ (383 mg, 2.74 mmol). The flask was sealed with a rubber septum, and then evacuated and backfilled with argon. Dioxane (4 mL) and water (1 mL) were added and the reaction was heated to 90° C. for 16 h. The reaction was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 30% MeOH) to provide crude 6-(2-(methoxymethoxy)-4-((triisopropylsilyl)oxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (316 mg, 41%) as a brownish solid. MS m/z 558.6 [M+H]⁺.

Step 2

To a solution of 6-[2-(methoxymethoxy)-4-triisopropylsilyloxy-phenyl]-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (316 mg, 0.57 mmol) in dry THE (2 mL) was added a 1.0 M solution of TBAF in THF (1.1 mL, 1.1 mmol). The reaction mixture was stirred at room temperature for 10 min until TLC showed complete consumption of the starting material. The solvent was removed under reduced pressure, and the residue was purified by column chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 30% MeOH) to yield 3-(methoxymethoxy)-4-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)phenol (156 mg, 69%) as a tan oil.

Step 3

To a solution of 3-(methoxymethoxy)-4-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)phenol in CH₂Cl₂ (3 mL) were added N,N-bis(trifluoromethylsulfonyl)aniline (280 mg, 0.78 mmol) and Et₃N (0.16 mL, 1.2 mmol). The reaction was stirred for 16 h until UPLC showed complete conversion. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel eluting with a EtOAc/hexanes gradient (30-100% EtOAc) to give 3-(methoxymethoxy)-4-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)phenyl trifluoromethanesulfonate (154 mg, 74%). MS m/z 534.4 [M+H]⁺.

Step 4

An oven-dried flask was equipped with a magnetic stir bar and charged with 3-(methoxymethoxy)-4-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)phenyl trifluoromethanesulfonate (51 mg, 0.096 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (24 mg, 0.12 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 0.01 mmol), and K₂CO₃ (40 mg, 029 mmol). The flask was sealed with a rubber septum and then evacuated and backfilled with argon. Dioxane (2 mL) and water (0.5 mL) were added and the reaction was heated to 90° C. for 16 h. The reaction was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography eluting with a MeOH/CH₂Cl₂ gradient (0 to 30% MeOH) to provide 6-(2-(methoxymethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (40 mg, 90%). MS m/z 466.6 [M+H]⁺.

Step 5:

To a solution of 6-(2-(methoxymethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (40 mg, 0.086 mmol) in CH₂Cl₂ (1 mL), were added 2 drops of MeOH and HCl (4 mol/L) in 1,4-dioxane (43 μL, 0.17 mmol). The reaction was stirred for 16 h at room temperature. The solvents were removed under reduced pressure, and the product was purified by column chromatography eluting with a MeOH/CH₂Cl₂ gradient (5 to 30% MeOH) to provide 2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)-5-(1-methyl-¹H-pyrazol-4-yl)phenol.

MS m/z 422.5 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 9.37-9.43 (m, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.24 (dd, J=8.5, 1.8 Hz, 1H), 7.19 (d, J=1.8 Hz, 1H), 5.36-5.48 (m, 1H), 3.97 (s, 3H), 3.16 (s, 3H), 2.00-2.15 (m, 4H), 1.64 (s, 6H), 1.58 (s, 6H); 2Hs not observed (OH and NH).

Using the procedure described for Example 3, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 8 MS m/z 419.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.25 (br s, 1H), 9.09 (s, 1H), 8.58- 8.71 (m, 2H), 8.00 (d, J = 8.3 Hz, 1H), 7.65-7.76 (m, 2H), 7.41-7.43 (m, 1H), 7.40 (s, 1H), 5.10-5.32 (m, 1H), 3.13 (s, 3H), 1.98 (t, J = 13.0 Hz, 2H), 1.82 (dd, J = 13.0, 3.7 Hz, 2H), 1.50 (s, 6H), 1.45 (s, 6H); 1H not observed (NH or OH). 9 MS m/z 433.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.51 (d, J = 5.1 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.54-7.63 (m, 1H), 7.49 (dd, J = 5.1, 1.5 Hz, 1H), 7.38 (dd, J = 8.1, 1.5 Hz, 1H), 7.35-7.36 (m, 1H), 5.11-5.32 (m, 1H), 3.08 (s, 3H), 2.54 (s, 3H), 1.54 (dd, J = 12.1, 3.4 Hz, 2H), 1.47 (t, J = 12.1 Hz, 2H), 1.24 (s, 6H), 1.10 (s, 6H); 2Hs not observed (NH and OH). 60 MS m/z 420.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.61 (s, 1H), 9.28 (br d, J = 5.2 Hz, 1H), 9.16 (s, 1H), 8.10 (br dd, J = 5.6, 2.5 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.52 (dd, J = 8.4, 1.7 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 5.35-5.48 (m, 1H), 3.25 (s, 3H), 1.95- 2.09 (m, 4H), 1.66 (s, 6H), 1.56 (s, 6H); 2Hs not observed (NH and OH) 61 MS m/z 434.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.39 (s, 1H), 9.13 (s, 1H), 8.04 (br d, J = 7.9 Hz, 1H), 7.95 (s, 1H), 7.37-7.53 (m, 2H), 5.29-5.46 (m, 1H), 3.21 (s, 3H), 2.78 (s, 3H), 1.67-1.85 (m, 4H), 1.47 (s, 6H), 1.35 (s, 6H); 2Hs not observed (NH and OH) 70 MS m/z 419.1 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.91 (s, 1H), 8.59 (d, J = 4.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.48-7.52 (m, 1H), 7.30-7.33 (m, 2H), 5.19 (br s, 1H), 3.08 (s, 3H), 1.45-1.55 (m, 4H), 1.11 (s, 6H), 1.24 (s, 6H); 2Hs not observed (OH and NH) 74 MS m/z 423.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.11 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J = 1.1 Hz, 1H), 7.34-7.39 (m, 2H), 5.33-5.42 (m, 1H), 3.77- 3.83 (m, 3H), 3.21 (s, 3H), 1.84-1.99 (m, 4H), 1.59 (br s, 6H), 1.47 (br s, 6H); 1H not observed 77 MS m/z 392.5 [M + H]⁺. ¹H NMR (methanol-d₄): 8.41 (s, 2H), 7.66 (dd, J = 8.32, 1.60 Hz, 1H), 7.31 (d, J = 8.33 Hz, 1H), 7.28 (s, 1H), 6.00 (s, 1H), 5.98 (s, 1H), 3.1 (s, 3H), 2.58-2.51 (m, 1H), 2.39-2.06 (m, 9H), 2.07-1.88 (m, 1H), 1.89-1.76 (m, 1H); 3Hs not observed (2NHs and OH) 78 MS m/z 364.4 [M + H]+. ¹H NMR (methanol-d₄): 8.91 (s, 1H), 7.90 (s, 2H), 7.72, (d, J = 8.09 Hz, 1H), 7.12 (d, J = 8.00 Hz, 1H), 7.09, (s, 1H), 4.11-4.07 (m, 1H), 4.00-3.96 (m, 2H), 2.39-2.35 (m, 2H), 2.29-2.25 (m, 4H), 2.17-2.01 (m, 4H); 2Hs not observed (OH and NH) 86 MS m/z 420.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.21 (s, 1H), 9.15 (s, 2H), 9.10 (s, 1H), 8.36 (br s, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.38-7.42 (m, 2H), 5.23 (br s, 1H), 3.11 (s, 3H), 1.81-1.89 (m, 2H), 1.67-1.71 (m, 2H), 1.41 (s, 6H), 1.33 (s, 6H); 1H not observed (OH or NH) 103 MS m/z 434.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.35 (s, 1H), 7.87-7.90 (m, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.17-7.19 (m, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.21 (br s, 1H), 3.10 (s, 3H), 1.66-1.82 (m, 4H), 1.39 (s, 6H), 1.30 (s, 6H); 2Hs not observed (OH and NH) 104 MS m/z 435.1 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.84 (dd, J = 9.6, 2.8 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H), 7.17 (dd, J = 8.0, 1.6 Hz, 2H), 7.13 (d, J = 1.6 Hz, 2H), 6.44 (d, J = 9.2 Hz, 1H), 5.19 (br s, 1H), 3.17 (s, 3H), 1.48- 1.58 (m, 4H), 1.27 (s, 6H), 1.14 (s, 6H); 1H not observed (OH or NH) 124 MS m/z 422.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.11 (br s, 1H), 7.88 (br d, J = 5.8 Hz, 1H), 7.52 (d, J = 1.5 Hz, 1H), 6.94-7.09 (m, 2H), 6.42 (d, J = 1.5 Hz, 1H), 5.24-5.42 (m, 1H), 3.94 (s, 3H), 3.16 (s, 3H), 1.70 (dd, J = 12.5, 3.4 Hz, 2H), 1.62 (t, J = 12.5 Hz, 2H), 1.38 (s, 6H), 1.26 (s, 6H); 2Hs not observed (NH and OH) 131 MS m/z 458.7 [M + H]⁺; ¹H NMR (DMSO- d₆) δ: 12.60 (br s, 1H), 11.30 (br s, 1H), 9.08 (s, 1H), 8.28 (s, 1H), 7.60-8.00 (m, 3H), 7.52 (br s, 1H), 7.28-7.31 (m, 2H), 5.21 (br s, 1H), 3.15 (s, 3H), 1.35-1.55 (m, 4H), 1.24 (s, 6H), 1.00 (s, 6H) 176 MS m/z 473.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.09 (s, 1H), 8.90 (d, J = 2.0 Hz, 1H), 8.51 (d, J = 2.0 Hz, 1H), 8.38 (br s, 2H), 8.23 (s, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.34- 7.36 (m, 2H), 5.21 (m, 1H), 4.11 (s, 3H), 3.17 (s, 3H), 1.60-1.70 (m, 4H), 1.33 (s, 6H), 1.15 (s, 6H) 177 MS m/z 472.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.09 (s, 1H), 8.40 (s, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.74 (s, 2H), 7.30-7.32 (m, 2H), 5.21 (m, 1H), 4.08 (s, 3H), 3.10 (s, 3H), 1.63-1.78 (m, 4H), 1.37 (s, 6H), 1.27 (s, 6H); 1H not observed (OH or NH) 188 MS m/z 462.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.09 (s, 1H), 7.82-7.87 (m, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.15 (d, J = 7.6 Hz, 3H), 6.90 (d, J = 7.9 Hz, 1H), 6.00 (s, 2H), 5.29-5.44 (m, 1H), 3.19 (s, 3H), 1.84-1.96 (m, 4H), 1.56 (s, 6H), 1.44 (s, 6H); 2Hs not observed (NH and OH) 352 MS m/z 395.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 8.98 (s, 1H), 8.41 (br s, 1H), 8.25 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.54 (dd, J = 8.0, 1.6 Hz, 1H), 7.41 (s, 1H), 4.38 (br s, 1H), 1.98 (d, J = 1.6 Hz, 2H), 1.39-1.54 (m, 2H), 1.27 (s, 6H), 1.02 (s, 6H); 2Hs not observed (OH and NH)

Example 4 Preparation of Compound 23

Step 1

A suspension of 3-(methoxymethoxy)-4-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)phenyl trifluoromethanesulfonate (30 mg, 0.056 mmol, 1.0 equiv), B₂Pin₂ (20 mg, 0.078 mmol, 1.4 equiv), Pd(dppf)Cl₂ (4.6 mg, 0.0056 mmol, 0.1 equiv), and dry KOAc (16 mg, 0.168 mmol, 3.0 equiv) in dioxane (0.9 mL) was sparged with argon for 10 minutes, then heated to 90° C. under argon atmosphere for 2 h, after which complete conversion to 6-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine was observed. The reaction mixture was then cooled to room temperature and used directly in the next step.

Alternatively, 6-(4-chloro-2-(methoxymethoxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine could be used as a starting material for step 1. XPhos Pd G3 (10 mol %) could be used as catalyst in this case, otherwise following the above procedure.

Step 2

To the mixture from Step 1 was added aq. K₂CO₃ (85 μL, 2M, 3.0 equiv), 4-bromo-2-methyl-2H-1,2,3-triazole (13.6 mg, 0.084 mmol, 1.5 equiv), and Pd(dppf)Cl₂ (4.6 mg, 0.0056 mmol, 0.1 equiv). The mixture was then heated to 95° C. under argon for 12 h. The reaction was cooled to room temperature, filtered over Celite (washed with 10% MeOH/CH₂Cl₂), concentrated, and purified by column chromatography eluting with MeOH/CH₂Cl₂ (5-15% MeOH) to afford 6-(2-(methoxymethoxy)-4-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine which was used in the next step without further purification.

Step 3:

6-(2-(Methoxymethoxy)-4-(2-methyl-2H-1,2,3-triazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine from Step 2 was dissolved in MeOH (0.5 mL), then HCl (0.5 mL, 4M in dioxane) was added. The solution was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by column chromatography eluting with MeOH/CH₂Cl₂ (10-30% MeOH) to afford 2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)-5-(2-methyl-2H-1,2,3-triazol-4-yl)phenol (11.5 mg, 50% over 3 steps).

MS m/z 423.3 [M+H]⁺ ¹H NMR (methanol-d) δ: 9.12 (s, 1H), 8.04 (s, 1H), 7.87-7.96 (m, 1H), 7.42-7.51 (m, 2H), 5.36-5.45 (m, 1H), 4.25 (s, 3H), 3.23 (s, 3H), 1.90-2.07 (m, 4H), 1.65 (s, 6H), 1.53 (s, 6H); 2Hs not observed (NH and OH).

Using the procedure described for Example 4, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 2 MS m/z 450.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.87 (d, J = 1.0 Hz, 1H), 8.35 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.75 (dd, J = 8.3, 1.7 Hz, 1H), 7.48 (d, J = 1.0 Hz, 1H), 5.13-5.30 (m, 1H), 3.99 (s, 3H), 3.09 (s, 3H), 1.59 (d, J = 7.8 Hz, 4H), 1.29 (s, 6H), 1.17 (s, 6H); 1H not observed (NH or OH). 3 MS m/z 449.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.33 (s, 1H), 8.25 (d, J = 5.4 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.33-7.40 (m, 2H), 7.30 (dd, J = 5.4, 1.5 Hz, 1H), 7.09 (d, J = 0.9 Hz, 1H), 5.11-5.32 (m, 1H), 3.90 (s, 4H), 3.10 (s, 3H), 1.60-1.79 (m, 3H), 1.35 (s, 6H), 1.25 (s, 6H); 1H not observed (NH or OH). 4 MS m/z 409.1 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.33 (br. s., 2H), 9.06 (s, 1H), 8.37 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.45 (dd, J = 8.2, 1.6 Hz, 1H), 5.05-5.34 (m, 1H), 3.08 (s, 3H), 1.54 (dd, J = 12.0, 3.7 Hz, 2H), 1.48 (t, J = 12.0 Hz, 2H), 1.24 (s, 6H), 1.11 (s, 6H); 1H not observed (NH or OH). 5 MS m/z 435.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.65 (br. s., 1H), 11.12 (br. s., 1H), 9.06 (s, 1H), 8.80 (br. s., 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 6.8 Hz, 1H), 7.28 (dd, J = 8.3, 1.7 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 6.56 (d, J = 1.6 Hz, 1H), 6.48 (dd, J = 6.8, 1.6 Hz, 1H), 5.06- 5.35 (m, 1H), 3.34 (s, 3H), 1.75-2.02 (m, 4H), 1.48 (s, 6H), 1.40 (s, 6H). 6 MS m/z 422.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.06 (s, 1H), 8.38 (br. s., 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.07 (dd, J = 8.2, 1.6 Hz, 1H), 5.07-5.28 (m, 1H), 3.10 (s, 3H), 2.41 (s, 3H), 1.85 (t, J = 12.5 Hz, 2H), 1.69 (dd, J = 12.5, 3.5 Hz, 2H), 1.41 (s, 6H), 1.33 (s, 6H); 2Hs not observed (NH and OH). 7 MS m/z 409.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.02 (s, 1H), 8.25 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.41 (s, 1H), 5.09-5.37 (m, 1H), 3.08 (s, 3H), 1.41-1.61 (m, 4H), 1.24 (s, 6H), 1.11 (s, 6H); 2Hs not observed (NH and OH). 12 MS m/z 426.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.09 (s, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.22-7.20 (m, 2H), 5.36 (dt, J = 17.0, 9.0 Hz, 1H), 3.20 (s, 3H), 1.96 (d, J = 8.0 Hz, 4H), 1.61 (s, 6H), 1.50 (s, 6H); 3Hs not observed (2NHs and OH). 18 MS m/z 440.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.10 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.14-7.23 (m, 2H), 5.32-5.39 (m, 1H), 3.83 (s, 3H), 3.20 (s, 3H), 1.91-2.00 (m, 4H), 1.61 (s, 6H), 1.50 (s, 6H); 2H not observed (NH and OH). 53 MS m/z 424.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 8.97 (s, 1H), 7.82 (d, J = 8.09 Hz, 1H), 7.52 (dd, J = 5.04, 0.92 Hz, 1H), 7.47 (dd, J = 3.51, 0.91 Hz, 1H), 7.22-7.17 (m, 2H), 7.09-7.07 (m, 1H), 5.21-5.08 (m, 1H), 3.03 (s, 3H), 2.00- 1.66 (m, 4H), 1.38, (s, 12H); 2Hs not observed (NH and OH) 54 MS m/z 438.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.05 (s, 1H), 7.89 (d, J = 8.09 Hz, 1H), 7.37 (s, 1H), 7.25 (dd, J = 8.24, 1.53 Hz, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 5.28- 5.17 (m, 1H), 3.12 (s, 3H), 2.27 (s, 3H), 2.04-1.74 (m, 4H), 1.38, (s, 12H); 2Hs not observed (NH and OH). 56 MS m/z 449.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.06 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.28-7.31 (m, 2H), 6.64 (d, J = 2.0 Hz, 1H), 6.55 (dd, J = 7.2, 2.0 Hz, 1H), 5.23 (br s, 1H), 3.92 (s, 3H), 3.11 (s, 3H), 1.83-1.91 (m, 2H), 1.68-1.73 (m, 2H), 1.43 (s, 6H), 1.37 (s, 6H); 2Hs not observed (OH and NH) 57 MS m/z 442.5 [M + H]+, 444.5 [M + 2 + H]⁺; ¹H NMR (methanol-d₄) δ: 9.09 (s, 1H), 8.29 (s, 1H), 7.92 (d, J = 11.0 Hz, 1H), 7.55-7.64 (m, 1H), 7.27-7.40 (m, 1H), 5.25-5.42 (m, 1H), 3.17 (s, 3H), 1.70 (ddd, J = 8.7, 5.3, 3.8 Hz, 2H), 1.60 (dd, J = 14.6, 12.5 Hz, 2H), 1.40 (s, 6H), 1.27 (s, 6H); 3Hs not observed (2 NHs and OH) 58 MS m/z 425.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.14 (s, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.95-8.00 (m, 1H), 7.92 (d, J = 3.4 Hz, 1H), 7.67 (d, J = 3.2 Hz, 1H), 7.57-7.61 (m, 2H), 5.35-5.46 (m, 1H), 3.25 (s, 3H), 2.01 (s, 4H), 1.66 (s, 6H), 1.55 (s, 6H); 1H not observed (NH or OH) 62 MS m/z 423.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.04 (s, 1H), 8.55 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.59 (dd, J = 7.9, 1.5 Hz, 1H), 5.18- 5.29 (m, 1H), 3.94 (s, 3H), 3.13 (s, 3H), 1.94-2.06 (m, 2H), 1.75- 1.87 (m, 2H), 1.52 (s, 6H), 1.48 (s, 6H); 2Hs not observed (OH and NH) 64 MS m/z 439.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 8.78 (s, 1H), 8.20 (s, 1H), 7.82 (d, J = 7.93 Hz, 1H), 7.40 (s, 1H), 7.31 (d, J = 8.01, 1.60 Hz, 1H), 5.31-5.15 (m, 1H), 3.94 (s, 3H), 3.11 (s, 3H), 2.09-1.7 (m, 4H), 1.46 (s, 12H); 2Hs not observed (NH and OH) 65 MS m/z 426.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.15 (s, 1H), 8.81 (s, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.65-7.70 (m, 2H), 5.34-5.47 (m, 1H), 3.25 (s, 3H), 1.96-2.03 (m, 4H), 1.64 (s, 6H), 1.53 (s, 6H); 2Hs not observed (NH and OH). 66 MS m/z 440.5 [M + H]⁺; ¹H NMR (chloroform-d) δ: 9.12 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.96-8.04 (m, 1H), 7.57- 7.62 (m, 2H), 5.29-5.46 (m, 1H), 3.22 (s, 3H), 2.69 (s, 3H), 1.93-2.01 (m, 4H), 1.61 (s, 6H), 1.50 (s, 6H); 1H not observed (NH or OH) 71 MS m/z 419.1 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.69 (d, J = 4.4 Hz, 1H), 8.38 (br s, 1H), 7.94-7.98 (m, 2H), 7.87-7.92 (m, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.66 (dd, J = 6.4, 1.6 Hz, 1H), 7.36-7.40 (m, 1H), 5.23 (br s, 1H), 3.10 (s, 3H), 1.75-1.82 (m, 2H), 1.64-1.68 (m, 2H), 1.38 (s, 6H), 1.29 (s, 6H); 1H not observed (OH or NH) 75 MS m/z 422.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.10 (s, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.69 (s, 1H), 7.54 (d, J = 1.1 Hz, 1H), 7.34-7.38 (m, 2H), 5.32-5.46 (m, 1H), 3.80 (s, 3H), 3.21 (s, 3H), 1.87-1.98 (m, 4H), 1.59 (s, 6H), 1.47 (s, 6H); 2Hs not observed (NH and OH) 76 MS m/z 422.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.00 (s, 1H), 7.75 (d, J = 7.78 Hz, 1H), 7.52 (d, J = 2.29 Hz, 1H), 7.31 (s, 1H), 7.29 (s, 1H), 6.55 (d, J = 2.29 Hz, 1H), 5.37-5.18 (m, 1H), 3.84 (s, 3H), 3.11 (s, 3H), 1.91-1.83 (m, 4H), 1.53 (s, 6H), 1.42 (s, 6H); 2Hs not observed (NH and OH) 80 MS m/z 459.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.15-9.18 (m, 1H), 9.10 (br d, J = 13.3 Hz, 2H), 8.10-8.15 (m, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.86 (s, 1H), 7.69-7.72 (m, 1H), 7.63 (d, J = 7.0 Hz, 1H), 5.35-5.46 (m, 1H), 3.25 (s, 3H), 1.99-2.09 (m, 4H), 1.66 (s, 6H), 1.56 (s, 6H); 2Hs not observed (NH and OH) 81 MS m/z 424.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ 9.13 (s, 1H), 7.98-8.12 (m, 1H), 7.55-7.72 (m, 2H), 5.34-5.47 (m, 1H), 3.24 (s, 3H), 2.66 (s, 3H), 1.86-2.01 (m, 4H), 1.62 (s, 6H), 1.51 (s, 6H); 2Hs not observed (OH and NH) 83 MS m/z 420.1 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.27 (d, J = 1.2 Hz, 1H), 9.07 (s, 1H), 8.74 (dd, J = 2.4, 1.6 Hz, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.74 (dd, J = 8.4, 1.6 Hz, 1H), 5.21 (br s, 1H), 3.09 (s, 3H), 1.45-1.58 (m, 4H), 1.25 (s, 6H), 1.06 (s, 6H); 2Hs not observed (OH and NH) 84 MS m/z 420.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.23 (dd, J = 4.8, 1.2 Hz, 1H), 9.09 (s, 1H), 8.36 (br s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.70-7.82 (m, 1H), 7.72 (dd, J = 8.4, 1.6 Hz, 1H), 5.23 (br s, 1H), 3.07 (s, 3H), 1.78-1.85 (m, 2H), 1.67-1.71 (m, 2H), 1.40 (s, 6H), 1.24 (s, 6H); 1H not observed (OH or NH) 85 MS m/z 420.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.05 (s, 1H), 8.93 (d, J = 4.8 Hz, 2H), 8.06 (s, 1H), 7.99 (s, 2H), 7.47 (t, J = 4.8 Hz, 1H), 5.23 (br s, 1H), 3.08 (s, 3H), 1.44-1.56 (m, 4H), 1.25 (s, 6H), 1.11 (s, 6H); 2Hs not observed (OH and NH) 88 MS m/z 451.6 [M + H]⁺; ¹H NMR (methanol- d₄) δ: 9.08-9.24 (m, 1H), 8.95 (s, 1H), 8.00 (s, 1H), 7.78-7.92 (m, 2H), 5.27-5.42 (m, 1H), 3.37 (s, 3H), 3.16 (s, 3H), 1.53- 1.76 (m, 4H), 1.36 (s, 6H), 1.24 (s, 6H); 2Hs not observed (NH and OH) 91 MS m/z 409.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.09 (s, 1H), 8.29 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.59 (s, 1H), 7.29-7.41 (m, 2H), 5.29-5.40 (m, 1H), 3.18 (s, 3H), 1.64-1.80 (m, 4H), 1.42 (s, 6H), 1.30 (s, 6H); 2Hs not observed (NH and OH) 92 MS m/z 459.6 [M + H]+; ¹H NMR (methanol-d₄) δ: 9.17 (s, 1H), 8.22 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.79-7.85 (m, 2H), 7.69-7.74 (m, 2H), 5.41 (br s, 1H), 3.25 (s, 3H), 1.96-2.03 (m, 4H), 1.65 (s, 6H), 1.53 (s, 6H); 2Hs not observed (NH and OH) 97 MS m/z 458.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ 9.37 (br d, J = 10.38 Hz, 1H), 9.09 (s, 1H), 8.29 (br d, J = 10.83 Hz, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.94 (d, J = 7.93 Hz, 1H), 7.62- 7.70 (m, 2H), 7.28-7.33 (m, 2H), 5.23 (br s, 1H), 3.12 (s, 3H), 2.06 (br t, J = 12.82 Hz, 2H), 1.74-1.82 (m, 2H), 1.52 (s, 6H), 1.50 (s, 6H); 1H not observed (NH or OH) 98 MS m/z 437.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.68-8.73 (m, 1H), 7.91-8.00 (m, 2H), 7.80 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.32 (br s, 1H), 5.21 (br s, 1H), 3.08 (s, 3H), 1.44-1.55 (m, 4H), 1.24 (s, 6H), 1.03 (s, 6H); 2Hs not observed (OH and NH) 101 MS m/z 448.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.09- 9.11 (m, 1H), 8.09-8.13 (m, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.19 (dd, J = 6.6, 1.5 Hz, 1H), 7.17 (d, J = 1.7 Hz, 1H), 5.32-5.43 (m, 1H), 3.72 (tt, J = 7.3, 3.8 Hz, 1H), 3.22 (s, 3H), 1.97-2.00 (m, 4H), 1.63 (s, 6H), 1.52 (s, 6H), 1.14-1.18 (m, 2H), 1.07-1.13 (m, 2H); 2Hs not observed (NH and OH) 102 MS m/z 420.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.27 (s, 1H), 9.07 (s, 1H), 8.87 (d, J = 5.2 Hz, 1H), 8.36 (br s, 1H), 8.08 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 5.23 (br s, 1H), 3.17 (s, 3H), 1.63-1.75 (m, 4H), 1.35 (s, 6H), 1.25 (s, 6H); 1H not observed (OH or NH) 106 MS m/z 410.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.14 (s, 1H), 9.06 (s, 1H), 8.06 (d, J = 7.3 Hz, 1H), 7.63-7.75 (m, 2H), 5.31-5.48 (m, 1H), 3.22 (s, 3H), 1.74-1.96 (m, 4H), 1.54 (s, 6H), 1.42 (s, 6H); 2Hs not observed (OH and NH) 107 MS m/z 395.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.27 (s, 1H), 8.82 (d, J = 12.0 Hz, 1H), 8.10 (d, J = 12.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.51 (s, 1H), 7.44 (dd, J = 8.0, 1.5 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 5.67-5.61 (m, 1H), 2.37 (dd, J = 13.5, 4.0 Hz, 2H), 1.82 (t, J = 12.0 Hz, 2H), 1.51 (s, 6H), 1.47 (s, 6H) 108 MS m/z 409.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.27 (s, 1H), 9.02 (d, J = 11.5 Hz, 1H), 8.25 (d, J = 11.5 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 2.0, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.41 (dd, J = 8.0, 1.5 Hz, 1H), 6.70 (d, J = 2.0 Hz, 1H), 5.65-5.60 (m, 1H), 3.90 (s, 3H), 2.35 (dd, J = 13.0, 3.5 Hz, 2H), 1.84 (t, J = 12.5 Hz, 2H), 1.52 (s, 6H), 1.49 (s, 6H) 111 MS m/z 408.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.13 (s, 1H), 7.91 (d, J = 8.09 Hz, 1H), 7.71 (s, 1H), 7.43 (s, 2H), 6.73 (s, 1H), 5.42-5.35 (m, 1H), 3.23 (s, 3H), 2.04-1.97 (m, 4H), 1.66 (s, 6H), 1.54 (s, 6H); 3Hs not observed (2 NHs and OH) 112 MS m/z 438.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.12-9.13 (m, 1H), 8.81 (s, 2H), 8.00-8.03 (m, 2H), 7.95 (d, J = 8.5 Hz, 1H), 5.32-5.43 (m, 1H), 3.21 (s, 3H), 1.77-1.88 (m, 4H), 1.50 (s, 6H), 1.38 (s, 6H); 2Hs not observed (NH and OH) 123 MS m/z 454.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.15 (s, 1H), 8.22 (d, J = 8.9 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.76 (s, 1H), 7.71 (br d, J = 8.2 Hz, 1H), 5.32-5.45 (m, 1H), 3.22 (s, 3H), 1.85-1.92 (m, 4H), 1.55 (s, 6H), 1.43 (s, 6H); 2Hs not observed (NH and OH) 128 MS m/z 434.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.14 (s, 1H), 8.73 (s, 2H), 7.98-8.01 (m, 2H), 7.97 (s, 1H), 5.34- 5.46 (m, 1H), 3.23 (s, 3H), 2.40 (s, 3H), 1.96-2.00 (m, 4H), 1.62 (s, 6H), 1.51 (s, 6H); 2Hs not observed (NH and OH) 129 MS m/z 434.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.17 (s, 1H), 8.69 (d, J = 4.9 Hz, 1H), 8.01-8.07 (m, 2H), 7.98 (s, 1H), 7.28-7.31 (m, 1H), 5.36-5.45 (m, 1H), 3.24 (s, 3H), 2.62 (s, 3H), 1.99-2.05 (m, 4H), 1.66 (s, 6H), 1.55 (s, 6H); 2Hs not observed (NH and OH) 130 MS m/z 454.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.15 (s, 1H), 8.70 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 9.6 Hz, 1H), 7.97 (d, J = 5.2 Hz, 1H), 7.78-7.85 (m, 2H), 5.34- 5.46 (m, 1H), 3.24 (s, 3H), 1.92-1.98 (m, 4H), 1.60 (s, 6H), 1.49 (s, 6H); 2Hs not observed (NH and OH) 132 MS m/z 459.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.10 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.39 (br s, 1H), 8.22 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.33-7.36 (m, 2H), 5.23 (br s, 1H), 3.11 (s, 3H), 1.74-1.82 (m, 2H), 1.64-1.67 (m, 2H), 1.38 (s, 6H), 1.29 (s, 6H); 2Hs not observed (OH and NH) 134 MS m/z 436.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.19-9.38 (m, 1H), 8.05 (d, J = 10.1 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.32 (s, 1H), 7.20 (dd, J = 7.9, 1.2 Hz, 1H), 7.07 (d, J = 10.1 Hz, 1H), 5.28-5.38 (m, 1H), 3.16 (s, 3H), 1.68 (br dd, J = 12.8, 2.2 Hz, 2H), 1.61 (t, J = 12.8 Hz, 2H), 1.37 (s, 6H), 1.25 (s, 6H); 3Hs not observed (NH and 2 OHs) 136 MS m/z 459.1 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 13.40 (br s, 1H), 11.30 (br s, 1H), 9.07 (s, 1H), 8.37 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.97-8.00 (m, 2H), 7.82 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 5.19-5.22 (m, 1H), 3.08 (s, 3H), 1.44-1.55 (m, 4H), 1.25 (s, 6H), 1.11 (s, 6H); 1H not observed (OH or NH) 141 MS m/z 487.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.14 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.92 (s, 1H), 7.62- 7.67 (m, 2H), 7.57 (s, 1H), 5.34-5.46 (m, 1H), 3.24 (s, 3H), 2.68 (s, 3H), 2.50 (s, 3H), 1.98-2.05 (m, 4H), 1.66 (s, 6H), 1.56 (s, 6H); 2Hs not observed (NH and OH) 142 MS m/z 473.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.16 (s, 1H), 7.93-8.04 (m, 3H), 7.72 (d, J = 10.2 Hz, 1H), 7.65-7.70 (m, 2H), 5.34-5.47 (m, 1H), 3.25 (s, 3H), 2.51 (s, 3H), 2.01 (br d, J = 7.8 Hz, 4H), 1.65 (s, 6H), 1.55 (s, 6H); 2Hs not observed (NH and OH) 143 MS m/z 424.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.01-9.14 (m, 2H), 7.99-8.11 (m, 2H), 7.72 (d, J = 1.5 Hz, 1H), 7.65 (dd, J = 8.2, 1.5 Hz, 1H), 5.18-5.30 (m, 1H), 4.45 (s, 3H), 3.14 (s, 3H), 2.01 (t, J = 13.0 Hz, 2H), 1.78-1.87 (m, 2H), 1.52 (s, 6H), 1.48 (s, 6H) 144 MS m/z 451.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.16 (s, 1H), 8.04 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 1.5 Hz, 1H), 7.70 (dd, J = 8.2, 1.5 Hz, 1H), 5.36-5.46 (m, 1H), 4.23 (s, 3H), 3.25 (s, 3H), 1.94-2.08 (m, 4H), 1.65 (s, 6H), 1.54 (s, 6H); 2Hs not observed (NH and OH) 145 MS m/z 459.0 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.09 (s, 1H), 8.80 (s, 1H), 8.10 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.73 (dd, J = 8.4, 1.6 Hz, 1H), 7.33-7.37 (m, 2H), 5.20 (br s, 1H), 3.09 (s, 3H), 1.44-1.56 (m, 4H), 1.24 (s, 6H), 1.09 (s, 6H); 2Hs not observed (OH and NH) 146 MS m/z 450.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.20-9.27 (m, 1H), 9.07 (s, 1H), 8.58 (s, 1H), 8.14-8.22 (m, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.63 (dd, J = 8.2, 1.8 Hz, 1H), 6.93 (s, 1H), 5.18-5.30 (m, 1H), 3.45 (s, 3H), 3.13 (s, 3H), 2.04 (t, J = 12.8 Hz, 2H), 1.79-1.84 (m, 2H), 1.52 (s, 6H), 1.49 (s, 6H) 147 MS m/z 450.6 [M + H]⁺; ¹H NMR (DMSO- d₆) δ: 9.17-9.27 (m, 1H), 9.10 (s, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.12-8.21 (m, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.43 (dd, J = 8.1, 1.7 Hz, 1H), 7.39 (d, J = 1.5 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 5.18-5.30 (m, 1H), 3.70 (s, 3H), 3.13 (s, 3H), 2.04 (t, J = 12.8 Hz, 2H), 1.78-1.84 (m, 2H), 1.52 (s, 6H), 1.49 (s, 6H) 152 MS m/z 459.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.16 (d, J = 7.6 Hz, 1H), 9.12 (s, 1H), 8.90-8.98 (m, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.90-7.98 (m, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 5.17-5.30 (m, 1H), 3.14 (s, 3H), 1.95-2.05 (m, 2H), 1.80-1.89 (m, 2H), 1.52 (s, 6H), 1.47 (s, 6H) 155 MS m/z 460.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.40 (d, J = 7.0 Hz, 1H), 9.09-9.15 (m, 2H), 8.53 (s, 1H), 8.03- 8.12 (m, 2H), 7.80 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.52 (s, 1H), 5.19-5.30 (m, 1H), 3.14 (s, 3H), 2.03 (t, J = 13.0 Hz, 2H), 1.83 (d, J = 12.5 Hz, 2H), 1.53 (s, 6H), 1.49 (s, 6H) 156 MS m/z 426.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.10 (s, 1H), 7.92 (d, J = 8.00 Hz, 1H), 7.68 (d, J = 4.00 Hz, 1H), 7.44 (s, 2H), 5.44-5.34, (m, 1H), 3.23 (s, 3H), 2.01 (d, J = 7.5 Hz, 4H), 1.65 (s, 6H), 1.54, (s, 6H); 3Hs not observed (2 NHs and OH) 158 MS m/z 459.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 12.16 (s, 1H), 9.07 (s, 1H), 8.86 (s, 1H), 8.38 (s, 1H), 7.97-7.99 (m, 1H), 7.92-7.93 (m, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.71-7.73 (m, 1H), 6.69 (d, J = 3.2 Hz, 1H), 5.21 (br s, 1H), 3.13 (s, 3H), 1.54-1.60 (m, 4H), 1.33 (s, 6H), 1.21 (s, 6H); 1H not observed (OH or NH) 163 MS m/z 473.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.65 (s, 1H), 9.11 (s, 1H), 8.41 (d, J = 8.54 Hz, 1H), 8.20 (d, J = 8.54 Hz, 1H), 8.03 (d, J = 8.09 Hz, 1H), 7.93 (s, 1H), 7.80 (d, J = 7.93 Hz, 1H), 5.26 (br s, 1H), 4.08 (s, 3H), 3.13 (s, 3H), 2.15 (t, J = 12.82 Hz, 2H) 1.75 (d, J = 12.36 Hz, 2H) 1.54 (s, 12H); 2Hs not observed (NH and OH) 164 MS m/z 473.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.09 (s, 1H), 8.48 (s, 1H), 8.14 (d, J = 8.09 Hz, 1H), 7.98 (d, J = 8.39 Hz, 1H), 7.92 (d, J = 8.39 Hz, 1H), 7.84-7.89 (m, 1H), 7.72 (d, J = 8.24 Hz, 1H), 5.26 (br s, 1H) 3.91 (s, 3 H), 3.13 (s, 3H), 2.11 (t, J = 12.82 Hz, 2H), 1.77 (d, J = 11.60 Hz, 2H), 1.54 (s, 6H), 1.53 (s, 6H); 2Hs not observed (NH and OH) 168 MS m/z 464.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.10-9.13 (m, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.18-7.26 (m, 2H), 6.58 (s, 1H), 5.34-5.44 (m, 1H), 3.23 (s, 3H), 2.21 (s, 3H), 1.98-2.05 (m, 4H), 1.65 (s, 6H), 1.56 (s, 6H); 5Hs not observed (3 NHs and 2 OHs) 169 MS m/z 488.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.13 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.80 (s, 1H), 7.66- 7.71 (m, 2H), 5.33-5.45 (m, 1H), 3.22 (s, 3H), 2.71 (s, 3H), 2.66-2.70 (m, 3H), 1.93 (t, J = 10.8 Hz, 4H), 1.59 (s, 6H), 1.47 (s, 6H); 2Hs not observed (NH and OH) 173 MS m/z 474.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.11 (s, 1H), 8.63 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 8.06-8.01 (m, 1H), 7.93 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 5.33-5.17 (m, 1H), 4.37 (s, 3H), 3.14 (s, 3H), 2.14-2.01 (m, 2H), 1.84-1.72 (m, 2H), 1.53 (s, 6H), 1.51 (s, 6H); 2Hs not observed (NH and OH) 178 MS m/z 461.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.24 (br s, 1H), 9.11 (s, 1H), 8.97-9.07 (m, 1H), 8.90 (d, J = 9.5 Hz, 1H), 8.45 (d, J = 9.5 Hz, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.93-8.07 (m, 1H), 7.87 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 5.15-5.35 (m, 1H), 3.15 (s, 3H), 1.97-2.06 (m, 2H), 1.80-1.88 (m, 2H), 1.53 (s, 6H), 1.48 (s, 6H); 1H from HCl salt 179 MS m/z 450.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.05 (br s, 1H), 9.15 (s, 1H), 9.07 (s, 1H), 8.00-8.08 (m, 2H), 7.87 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 5.74 (t, J = 5.8 Hz, 1H), 5.14-5.32 (m, 1H), 4.64 (d, J = 5.8 Hz, 2H), 3.13 (s, 2H), 1.88-2.03 (m, 2H), 1.73-1.85 (m, 2H), 1.48 (s, 6H), 1.43 (s, 6H); 2Hs not observed (OH and NH) 184 MS m/z 459.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 13.75 (br s, 1H), 11.24 (br s, 1H), 9.15 (s, 1H), 9.08 (s, 1H), 8.33 (d, J = 0.8 Hz, 1H), 8.31 (m, 1H), 8.28 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.69- 7.71 (m, 1H), 5.22 (br s, 1H), 3.42 (s, 3H), 1.63-1.64 (m, 4H), 1.33 (s, 6H), 1.21 (s, 6H) 185 MS m/z 469.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.31 (d, J = 8.00 Hz, 1H), 9.27-9.23 (m, 2H), 8.69 (s, 1H), 8.61-8.55 (m, 1H), 8.37 (d, J = 9.00 Hz, 1H), 8.20-8.16 (m, 1H), 8.06 (d, J = 8.00 Hz, 1H), 7.54 (d, J = 10 Hz, 1H), 7.52 (s, 1H), 5.47-5.37 (m, 1H), 3.19, (s, 3H), 2.19-2.01 (m, 4H), 1.65, (s, 6H), 1.57 (s, 6H); 2Hs not observed (NH and OH) 186 MS m/z 474.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.02 (s, 1H), 8.41 (d, J = 8.70 Hz, 1H), 8.15 (d, J = 8.70 Hz, 1H), 7.94 (d, J = 8.09 Hz, 1H), 7.84 (s, 1H), 7.72 (d, J = 8.09 Hz, 1H), 5.17 (br s, 1H), 4.30 (s, 3H), 3.05 (s, 3H), 1.99 (t, J = 12.89 Hz, 2H) 1.71 (d, J = 12.51 Hz, 2H), 1.45 (s, 6H), 1.42 (m, 6H); 2Hs not observed (NH and OH) 192 MS m/z 459.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.57 (br s, 1H), 9.42 (s, 1H), 9.12 (s, 1H), 8.45 (br s, 1H), 8.25 (s, 1H), 8.08 (d, J = 10.1 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 9.3, 1.4 Hz, 1H), 7.42-7.49 (m, 2H), 5.17-5.31 (m, 1H), 3.13 (s, 3H), 2.13 (t, J = 12.8 Hz, 2H), 1.73-1.80 (m, 2H), 1.54 (s, 6H), 1.53 (s, 6H) 194 MS m/z 460.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.22 (s, 1H), 9.08 (s, 1H), 8.52 (s, 1H), 8.34 (br s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.0, 2.0 Hz, 1H), 5.22 (br s, 1H), 3.14 (s, 3H), 1.60-1.69 (m, 4H), 1.32 (s, 6H), 1.21 (s, 6H); 2Hs not observed (OH and NH) 195 MS m/z 460.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.46 (s, 1H), 9.07 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H), 8.14 (d, J = 1.6 Hz, 1H), 8.05 (dd, J = 8.0, 1.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 5.24 (br s, 1H), 3.11 (s, 3H), 1.64-1.80 (m, 4H), 1.38 (s, 6H), 1.28 (s, 6H); 2Hs not observed (OH and NH) 198 MS m/z 473.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.37 (br s, 1H), 8.33 (s, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.73 (dd, J = 8.4, 1.6 Hz, 1H), 5.22 (br, 1H), 4.11 (s, 3H), 3.10 (s, 3H), 1.64-1.74 (m, 4H), 1.35 (s, 6H), 1.25 (s, 6H); 1H not observed (OH or NH) 200 MS m/z 473.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.20 (br s, 1H), 9.11 (s, 1H), 8.30 (s, 1H), 7.93-8.03 (m, 2H), 7.87-7.93 (m, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 5.18-5.28 (m, 1H), 4.36 (s, 3H), 3.13 (s, 3H), 1.81-1.90 (m, 2H), 1.69-1.81 (m, 2H), 1.46 (s, 6H), 1.38 (s, 6H); 1H not observed (OH or NH) 207 MS m/z 431.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.24-9.38 (m, 2H), 9.11-9.18 (m, 2H), 8.27 (d, J = 7.3 Hz, 2H), 8.01 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.42-7.49 (m, 2H), 4.05-4.21 (m, 3H), 3.80-3.93 (m, 4H), 1.41 (s, 9H) 208 MS m/z 444.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.04-9.25 (m, 3H), 8.13 (s, 1H), 8.05 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.74 (s, 2H), 7.29-7.38 (m, 2H), 4.13-4.25 (m, 3H), 4.09 (s, 3H), 3.76-3.97 (m, 4H), 1.40 (s, 9H) 209 MS m/z 392.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.29 (br s, 2H), 9.10 (s, 1H), 8.93 (dd, J = 4.7, 1.1 Hz, 2H), 8.09 (s, 1H), 7.96-8.03 (m, 2H), 7.44-7.51 (m, 1H), 4.05-4.22 (m, 3H), 3.77-3.98 (m, 4H), 1.41 (s, 9H) 210 MS m/z 395.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.17 (br s, 2H), 9.10 (s, 1H), 8.24 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 4.22 (s, 3H), 3.79-3.92 (m, 3H), 3.55-3.66 (m, 4H), 1.40 (s, 9H) 211 MS m/z 396.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.17 (br s, 2H), 9.10 (s, 1H), 8.24 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 4.22 (s, 3H), 3.79-3.92 (m, 3H), 3.55-3.66 (m, 4H), 1.40 (s, 9H); 1H from HCl salt 214 MS m/z 421.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 8.10 (d, J = 5.80 Hz, 1H), 7.79 (d, J = 7.78 Hz, 1H), 7.38 (d, J = 7.93 Hz, 1H), 7.35 (s, 1H), 7.23-7.21 (m, 1H), 7.16 (s, 1H), 6.01 (s, 1H), 4.36-4.32 (m, 1H), 4.12-4.17 (m, 1H), 3.99-3.88 (m, 2H), 3.84 (s, 3H), 3.79-3.71 (m, 1H), 2.66-2.69 (m, 1H), 2.41-2.48 (m, 1H), 1.51 (s, 9H); 2Hs not observed (NH and OH) 215 MS m/z 446.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.14 (s, 1H), 8.55-8.45 (m, 1H), 8.28-8.18 (m, 1H), 8.03- 7.97 (m, 1H), 7.93 (br s, 1H), 7.85-7.77 (m, 1H), 4.38 (s, 3H), 3.93-3.81 (m, 4H), 3.72-3.55 (m, 1H), 1.41 (s, 9H); (4Hs overlapped with residual solvent peaks) 216 MS m/z 422.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.13 (s, 1H), 7.83 (d, J = 8.09 Hz, 1H), 7.5-7.50 (m, 2H), 7.02 (s, 1H), 6.03 (s, 1H), 4.42-4.32 (m, 1H), 4.22-4.18 (m, 1H), 4.03-3.91 (m, 2H), 3.82-3.74 (m, 1H), 3.63-3.69 (m, 3H), 2.73-2.65 (m, 1H), 2.54-2.42 (m, 1H), 1.53 (s, 9H); 2Hs not observed (NH and OH) 217 MS m/z 422.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.16 (s, 1H), 8.81 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 4.31-4.21 (m, 2H), 4.06 (s, 3H), 4.01-3.97 (m,1H), 3.80-3.76 (m, 2H), 2.68-2.62 (m, 1H), 2.31-2.24 (m, 1H), 1.49 (s, 9H); 2Hs not observed (NH and OH) 221 MS m/z 445.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.16 (s, 1H), 8.89 (s, 1H), 8.49 (s, 1H), 8.17 (s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.29-7.38 (m, 2H), 4.18 (s, 4H), 3.99-4.07 (m, 1H), 3.92-3.99 (m, 1H), 3.67-3.77 (m, 1H), 3.54-3.63 (m, 1H), 2.47- 2.60 (m, 1H), 2.08-2.19 (m, 1H), 1.36-1.40 (m, 9H); 2Hs not observed (NH and OH) 222 MS m/z 473.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.19 (s, 1H), 9.13 (s, 1H), 8.41 (s, 1H), 8.15 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.58-7.66 (m, 2H), 5.36 (br d, J = 1.7 Hz, 1H), 4.35 (s, 3H), 3.19 (s, 3H), 1.66-1.83 (m, 4H), 1.45 (s, 6H), 1.32 (s, 6H); 2Hs not observed (NH and OH) 225 MS m/z 381.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.13 (s, 1H), 8.20 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.47- 7.46 (m, 2H), 4.26-4.18 (m, 2H), 3.99-3.95 (m, 1H), 3.75-3.72 (m, 2H), 2.65-2.59 (m, 1H), 2.30-2.23 (m, 1H), 1.47 (s, 9H); 1H not observed (NH or OH) 227 MS m/z 407.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 8.08 (d, J = 6.87 Hz, 1H), 7.80 (d, J = 8.24 Hz, 1H), 7.39 (d, J = 8.24 Hz, 1H), 7.36 (s, 1H), 7.18 (d, J = 6.71 Hz, 1H), 7.14 (s, 1H), 6.02 (d, J = 2.6 Hz, 1H), 4.38- 4.24 (m, 1H), 4.19-4.09 (m, 1H), 4.06-3.88 (m, 2H), 3.83-3.79 (m, 4H), 3.64-3.53 (m, 1H), 2.73-2.59 (m, 1H), 2.55-2.38 (m, 1H), 1.41-1.53 (m, 6H); 2Hs not observed (NH and OH) 234 MS m/z 408.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 8.76 (s, 1H), 7.70 (d, J = 8.09 Hz, 1H), 7.54-7.50 (m, 2H), 6.92 (s, 1H), 5.94 (m, 1H), 4.29-4.20 (m, 1H), 4.17-4.08 (m, 1H), 4.06-3.90 (m, 2H), 3.82-3.72 (m, 1H), 3.68-3.59 (m, 3H), 3.59-3.45 (m, 1H), 2.69-2.39 (m, 2H), 1.47 (br s, 6H); 2Hs not observed (NH and OH) 241 MS m/z 419.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 10.18 (br s, 1H), 9.04 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 6.64 (s, 1H), 6.54 (d, J = 7.0 Hz, 1H), 4.06 (br s, 2H), 3.98 (br s, 2H), 3.46 (s, 3H), 3.37 (m, 2H), 3.00 (dd, J = 22.1, 10.5 Hz, 2H), 2.74 (d, J = 4.43 Hz, 3H), 2.17 (d, 13.7 Hz, 2H), 2.00 (td, J = 13.7, 13.7, 3.5 Hz, 2H) 242 MS m/z 393.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.13 (br s, 1H), 9.29 (br s, 1H), 9.04 (s, 1H), 8.24 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H), 7.44 (d, J = 8.1 Hz, 1H), 4.22 (s, 3H), 4.06 (br s, 2H), 3.97 (br s, 2H), 3.42 (d, J = 12.05 Hz, 2H), 3.03 (dd, J = 22.3, 11.4 Hz, 2H), 2.79 (d, J = 4.0 Hz, 3H), 2.20 (d, J = 13.7 Hz, 2H), 1.90 (ddd, J = 14.8, 8.9, 3.4 Hz, 2H); 1H from TFA salt 243 MS m/z 420.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.10 (br s, 1H), 9.26 (br dd, J = 3.5, 2.0 Hz, 1H), 9.06 (s, 1H), 8.88 (s, 1H), 7.96 (br d, J = 8.1 Hz, 1H), 7.84 (s, 1H), 7.76 (br d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 4.07 (br s, 2H), 3.96- 4.01 (m, 5H), 2.99-3.07 (m, 2H), 2.77-2.82 (m, 3H), 2.18-2.25 (m, 2H), 1.84-1.95 (m, 2H); 2Hs not observed (CH₂ obscured by solvent peak); 1H from TFA salt 244 MS m/z 390.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 10.88 (br s, 1H), 9.25 (br s, 1H), 8.97 (s, 1H), 8.87 (d, J = 4.9 Hz, 2H), 8.00 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 4.7 Hz, 1H), 4.00 (br s, 2H), 3.91 (br s, 2H), 2.96 (dd, J = 22.1, 11.6 Hz, 2H), 2.73 (d, J = 4.1 Hz, 3H), 2.13 (d, J = 14.0 Hz, 2H) 1.83 (ddd, J = 14.2, 12.5, 3.4 Hz, 2H); 2Hs not observed (CH₂ obscured by solvent peak); 1H from TFA salt 245 MS m/z 379.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 15.02 (br s, 1H), 11.12 (br s, 1H), 9.21 (br s, 1H), 9.05 (s, 1H), 8.27 (br s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.51 (br s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 4.06 (br s, 2H), 3.97 (br s, 2H), 3.03 (dd, J = 22.4, 10.8 Hz, 2H), 2.79 (d, J = 4.6 Hz, 3H), 2.20 (d, J = 13.6 Hz, 2H), 1.90 (ddd, J = 14.0, 12.8, 4.3 Hz, 2H); 2Hs not observed (CH₂ obscured by solvent peak); 1H from TFA salt 246 MS m/z 454.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.88 (s, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.63-7.46 (m, 2H), 6.97 (s, 1H), 6.04 (d, J = 8.9 Hz, 1H), 3.64 (s, 3H), 2.22-2.01 (m, 2H), 1.76-1.65 (m, 6H), 1.64-1.51 (m, 6H); 4Hs not observed (2 NHs, OH and 1 CH obscured by solvent peak) 250 MS m/z 381.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.09 (s, 1H), 8.01 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.33 (s, 1H), 4.09-4.05 (m, 1H), 3.91- 3.88 (m, 1H), 3.81-3.74 (m, 1H), 3.66-3.60 (m, 1H), 3.42-3.36 (m, 1H), 2.44-2.37 (m, 1H), 2.02-1.94 (m, 1H), 1.25 (s, 9H); 2Hs not observed (NH and OH) 251 MS m/z 394.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.06 (br s, 1H), 9.28 (br s, 1H), 9.01 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 4.45 (s, 3H), 4.07 (br s, 2H), 3.98 (br s, 2H), 3.03 (dd, J = 22.1, 11.0 Hz, 2H), 2.79 (d, J = 4.1 Hz, 3H), 2.20 (d, J = 14.0 Hz, 2H), 1.90 (ddd, J = 14.6, 12.4, 2.6 Hz, 2H); 2Hs not observed (CH₂ obscured by solvent peak); 1H from TFA salt 252 MS m/z 379.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.08 (br s, 1H), 9.35 (br s, 1H), 9.00 (s, 1H), 8.24 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.41 (s, 1H), 4.06 (s, 2H), 3.96 (s, 2H), 3.02 (dd, J = 22.7, 10.8 Hz, 2H), 2.79 (d, J = 4.1 Hz, 3H), 2.20 (d, J = 14.0 Hz, 2H), 1.90 (ddd, J = 13.9, 13.0, 2.9 Hz, 2H); 2Hs not observed (CH₂ obscured by solvent peak); 1H from TFA salt 253 MS m/z 408.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.01 (s, 1H), 8.22 (m, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.35-7.38 (m, 1H), 6.70 (d, J = 2.4 Hz, 1H), 4.40 (br s, 1H), 3.89 (s, 3H), 2.02-2.09 (m, 2H), 1.46-1.54 (m, 2H), 1.44 (s, 6H), 1.35 (s, 6H); 2Hs not observed (OH and NH) 254 MS m/z 436.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.02 (s, 1H), 8.87 (s, 1H), 8.38 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 1.2 Hz ,1H), 7.73-7.76 (m, 1H), 7.48 (s, 1H), 4.35 (br s, 1H), 3.98 (s, 3H), 1.93-1.96 (m, 2H), 1.35-1.40 (m, 2H), 1.34 (s, 6H), 1.23 (s, 6H); 2Hs not observed (OH and NH) 258 MS m/z 367.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.17 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.84-7.77 (m, 1H), 7.74-7.72 (m, 2H), 4.25 (q, J = 6.3 Hz, 1H), 4.19 (dd, J = 12.1, 7.0 Hz, 1H), 4.03-3.99 (m, 1H), 3.86-3.78 (m, 2H), 3.63-3.57 (m, 1H), 2.63 (tt, J = 13.2, 6.3 Hz, 1H), 2.31 (dq, J = 14.2, 7.3 Hz, 1H), 1.45 (dd, J = 6.6, 4.0 Hz, 6H); 3Hs not observed (2NHs and OH) 259 MS m/z 382.2 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.14 (s, 1H), 8.20 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.48-7.46 (m, 2H), 4.23 (dt, J = 13.0, 7.0 Hz, 1H), 4.15 (dd, J = 12.5, 7.5 Hz, 1H), 3.98 (ddd, J = 11.5, 8.5, 5.5 Hz, 1H), 3.83-3.76 (m, 2H), 3.58 (quin, J = 6.5 Hz, 1H), 3.31 (s, 3H), 2.60 (td, J = 13.0, 7.5 Hz, 1H), 2.31-2.24 (m, 1H), 1.42 (dd, J = 6.5, 4.0 Hz, 6H); 1H not observed (NH or OH) 265 MS m/z 408.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.02-9.22 (m, 1H), 8.70-8.83 (m, 1H), 7.84-7.97 (m, 1H), 7.50- 7.67 (m, 2H), 7.22-7.38 (m, 1H), 4.05 (s, 3H), 3.93-4.01 (m, 1H), 3.82-3.91 (m, 1H), 3.61-3.70 (m, 2H), 3.36-3.46 (m, 1H), 2.94- 3.03 (m, 1H), 2.30-2.39 (m, 1H), 1.85-1.99 (m, 1H), 1.14 (t, J = 6.7 Hz, 6H); 2Hs not observed (NH and OH) 266 MS m/z 409.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.06-9.13 (m, 1H), 9.04 (s, 1H), 8.25 (s, 1H), 8.12 (br s, 1H), 7.94-8.01 (m, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 7.43 (dd, J = 8.2, 1.5 Hz, 1H), 4.36-4.46 (m, 1H), 4.22 (s, 3H), 2.05-2.12 (m, 2H), 1.62 (t, J = 12.7 Hz, 2H), 1.50 (s, 6H), 1.44 (s, 6H) 267 MS m/z 410.1 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.05-9.15 (m, 1H), 9.00 (s, 1H), 8.15 (br s, 1H), 7.92-8.03 (m, 2H), 7.72 (d, J = 1.5 Hz, 1H), 7.64 (dd, J = 8.2, 1.5 Hz, 1H), 4.33-4.50 (m, 4H), 2.02-2.16 (m, 2H), 1.62 (t, J = 12.8 Hz, 2H), 1.50 (s, 6H), 1.44 (s, 6H) 268 MS m/z 380.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.10 (s, 1H), 8.80 (s, 1H), 7.97 (d, J = 8 Hz, 1H), 7.65- 7.70 (m, 2H), 7.33 (s, 1H), 4.06 (s, 3H), 3.80-3.95 (m, 2H), 3.70- 3.78 (m, 1H), 3.52-3.59 (m, 1H), 3.43-3.48 (m, 1H), 2.47 (s, 3H), 2.29-2.35 (m, 1H), 2.00-2.04 (m, 1H); 2Hs not observed (NH and OH) 269 MS m/z 356.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.83 (s, 1H), 7.99 (d, J = 8 Hz, 1H), 7.61-7.72 (m, 2H), 6.04 (s, 1H), 4.03-4.15 (m, 2H), 3.78-3.95 (m, 2H), 3.50-3.54 (m, 1H), 2.65 (s, 3H), 2.58-2.66 (m, 1H), 2.42-2.53 (m, 1H); 2Hs not observed (NH and OH) 270 MS m/z 350.2 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.93 (d, J = 5.0 Hz, 2H), 8.02-8.05 (m, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 5.0 Hz, 1H), 6.05 (s, 1H), 4.06-4.16 (m, 2H), 3.75-3.85 (m, 2H), 3.60-3.70 (m, 1H), 2.85 (s, 3H), 2.61-2.69 (m, 1H), 2.40-2.57 (m, 1H); 2Hs not observed (NH and OH) 271 MS m/z 403.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.87 (d, J = 2 Hz, 1H), 8.53 (d, J = 2 Hz, 1H), 8.18 (d, J = 3.5 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.35 (dd, J = 8 Hz, 2 Hz, 1H), 7.32 (s, 1H), 6.01 (s, 1H), 4.16 (s, 3H), 4.00-4.15 (m, 2H), 3.88-3.95 (m, 2H), 3.80 (m, 1H), 2.84 (s, 3H), 2.60-2.70 (m, 1H), 2.35-2.50 (m, 1H); 2Hs not observed (NH and OH) 277 MS m/z 409.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 7.76 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.31 (s, 1H), 5.98 (s, 1H), 4.42-4.32 (m, 1H), 2.67 (s, 3H), 2.30-2.17 (m, 2H), 1.86-1.73 (m, 2H), 1.63 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H), 1.53 (s, 3H); 2Hs not observed (NH and OH) 279 MS m/z 406.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.01 (s, 1H), 8.92 (d, J = 5.2 Hz, 2H), 8.06 (s, 1H), 7.98 (s, 2H), 7.47 (t, J = 5.0 Hz, 1H), 4.41 (br s, 1H), 2.02-2.12 (m, 2H), 1.48-1.56 (m, 2H), 1.44 (s, 6H), 1.35 (s, 6H); 3Hs not observed (OH and 2NHs) 280 MS m/z 475.8 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.33 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.66 (br s, 1H), 7.29-7.37 (m, 3H), 6.56 (s, 1H), 6.32 (s, 1H), 5.20 (br s, 1H), 3.09 (s, 3H), 1.54-1.60 (m, 4H), 1.30 (s, 6H), 1.17 (s, 6H); 1H not observed (OH or NH) 281 MS m/z 474.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.58 (s, 1H), 9.05 (s, 1H), 8.45 (s, 1H), 8.12 (d, J = 1.6 Hz, 1H), 8.05 (dd, J = 8.0, 1.2 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 5.22 (br s, 1H), 4.23 (s, 3H), 3.05 (s, 3H), 1.47-1.58 (m, 4H), 1.26 (s, 6H), 1.06 (s, 6H); 2Hs not observed (OH and NH) 283 MS m/z 417.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.26 (s, 1H), 9.17 (s, 1H), 9.07 (s, 1H), 8.17 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 0.9 Hz, 1H), 7.71 (s, 1H), 7.61 (dd, J = 8.5, 1.5 Hz, 1H), 3.67-3.86 (m, 2H), 3.47-3.54 (m, 1H), 3.18-3.38 (m, 2H), 2.84 (dt, J = 12.4, 6.3 Hz, 1H), 2.10-2.23 (m, 1H), 1.74-1.89 (m, 1H), 1.02 (t, J = 6.4 Hz, 6H); 2Hs not observed (NH and OH) 284 MS m/z 477.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.82-9.94 (m, 1H), 9.11 (s, 1H), 8.90 (d, J = 2.1 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.29 (br s, 1H), 8.23 (s, 1H), 8.08-8.17 (m, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.34-7.40 (m, 2H), 4.70-4.87 (m, 2H), 4.11 (s, 3H), 1.95- 2.06 (m, 1H), 1.84-1.95 (m, 1H), 1.57 (d, J = 18.5 Hz, 6H), 1.48 (d, J = 6.4 Hz, 6H) 285 MS m/z 472.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.37 (br s, 2H), 8.25 (s, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.40 Hz, 1H), 7.31 (d, J = 7.6 Hz, 2H), 5.22 (br s, 1H), 4.03 (s, 3H), 3.10 (s, 3H), 1.64-1.77 (m, 4H), 1.33 (s, 6H), 1.06 (s, 6H) 287 MS m/z 427.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.97 (d, J = 10.7 Hz, 1H), 8.25 (s, 1H), 8.20 (br d, J = 12.7 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 8.0, 1.6 Hz, 1H), 4.83 (d, J = 49.0 Hz, 1H), 4.22 (s, 3H), 2.00 (br d, J = 13.3 Hz, 1H), 1.90-1.96 (m, 1H), 1.53 (br d, J = 19.2 Hz, 6H), 1.45 (br d, J = 5.5 Hz, 6H); 2Hs not observed (1 NH and 1 CH obscured by solvent peak) 288 MS m/z 413.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 10.95-11.09 (m, 1H), 8.91-8.99 (m, 2H), 8.19 (d, J = 0.6 Hz, 1H), 8.12 (br dd, J = 11.7, 1.4 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.51 (dd, J = 8.2, 1.7 Hz, 1H), 7.35 (d, J = 0.8 Hz, 1H), 4.71-4.86 (m, 1H), 1.90-1.98 (m, 1H), 1.83-1.90 (m, 1H), 1.46 (br d, J = 18.9 Hz, 6H), 1.38 (br d, J = 5.3 Hz, 6H); 1H not observed (1 CH obscured by solvent peak). 290 MS m/z 454.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.14 (bs, 1H), 9.08 (m, 2H), 8.88 (s, 1H), 8.20 (d, 12.5 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.76 (dd, J = 8.2, 1.7 Hz, 1H), 7.47 (s, 1H), 4.85 (bd, J = 47.3 Hz, 1H), 3.99 (s, 3H), 2.01 (t, J = 13.4 Hz, 1H), 1.93 (dd, J = 13.7, 3.6 Hz, 1H), 1.55 (s, 3H), 1.51 (s, 3H), 1.46 (d, J = 1.4 Hz, 3H), 1.44 (s, 3H); 1H not observed (1 CH obscured by solvent peak) 291 MS m/z 428.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.03 (s, 2H), 8.98 (d, J = 10.8 Hz, 1H), 8.20 (br d, J = 11.3 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 1.4 Hz, 1H), 7.66 (dd, J = 8.1, 1.7 Hz, 1H), 4.86 (d, J = 47.9 Hz, 1H), 4.45 (s, 3H), 2.02 (d, J = 13.6 Hz, 1H), 1.91-1.98 (m, 1H), 1.55 (s, 3H), 1.51 (s, 3H), 1.46 (br d, J = 0.9 Hz, 3H), 1.45 (s, 3H); 1H not observed (1 CH obscured by solvent peak) 292 MS m/z 430.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 10.96-11.45 (m, 1H), 9.02-9.10 (m, 2H), 9.00 (s, 1H), 8.20 (br d, J = 13.1 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 1.7 Hz, 1H), 7.65 (dd, J = 8.1, 1.7 Hz, 1H), 4.86 (d, J = 47.5 Hz, 1H), 2.02 (br t, J = 13.4 Hz, 1H), 1.94 (br dd, J = 13.7, 4.0 Hz, 1H), 1.55 (s, 3H), 1.51 (s, 3H), 1.46 (br s, 3H), 1.45 (s, 3H); 1H not observed (1 CH obscured by solvent peak) 294 MS m/z 417.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.13 (br s, 1H), 8.32 (br s, 1H), 8.10-8.24 (m, 1H), 7.92-8.00 (m, 1H), 7.73-7.83 (m, 2H), 7.43-7.57 (m, 2H), 3.69-3.84 (m, 2H), 3.45-3.60 (m, 3H), 2.79-2.89 (m, 1H), 2.10-2.25 (m, 1H), 1.74-1.88 (m, 1H), 1.34 (t, J = 6.1 Hz, 6H); 2Hs not observed (NH and OH) 295 MS m/z 353.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.23 (s, 1H), 7.91 (d, J = 8 Hz, 1H), 7.42- 7.48 (m, 2H), 4.20 (s, 3H), 3.75-4.00 (m, 4H), 3.65-3.75 (m, 1H), 2.66 (s, 3H), 2.40-2.50 (m, 1H), 2.29-2.35 (m, 1H); 2Hs not observed (NH and OH) 300 MS m/z 490.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.10 (s, 1H), 8.81 (d, J = 11.6 Hz, 1H), 8.41 (s, 1H), 7.89-7.96 (m, 2H), 7.80 (s, 1H), 7.47 (d, J = 12.8 Hz, 1H), 7.31-7.36 (m, 2H), 5.22 (br s, 1H), 4.03 (s, 3H), 3.13 (s, 3H), 1.93-2.00 (m, 2H), 1.83-1.87 (m, 2H), 1.51 (s, 6H), 1.44 (s, 6H 301 MS m/z 494.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.06 (s, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.16-7.20 (m, 2H), 5.22 (br s, 1H), 3.10 (s, 3H), 1.63-1.66 (m, 4H), 1.33 (s, 6H), 1.21 (s, 6H); 2Hs not observed (OH and NH) 302 MS m/z 508.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.06 (s, 1H), 8.35 (br s, 1H), 8.29 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 5.2 Hz, 1H), 7.20 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 5.20 (br s, 1H), 4.00 (s, 3H), 3.11 (s, 3H), 1.69-1.86 (m, 4H), 1.41 (s, 6H), 1.25 (s, 6H); 1H not observed (OH or NH) 303 MS m/z 473.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.16 (s, 1H), 8.54 (br s, 2H), 8.18 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 0.6 Hz, 1H), 7.66-7.70 (m, 3H), 5.38-5.42 (m, 1H), 3.24 (s, 3H), 2.72 (s, 3H), 1.92- 1.99 (m, 4H), 1.63 (s, 6H), 1.51 (s, 6H) 304 MS m/z 489.2 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.19 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.75-7.77 (m, 2H), 7.58 (s, 1H), 5.38-5.45 (m, 1H), 4.36 (s, 3H), 3.25 (s, 3H), 2.02 (d, J = 8.0 Hz, 4H), 1.66 (s, 6H), 1.54 (s, 6H); 2Hs not observed (OH and NH) 305 MS m/z 407.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.79 (s, 1H), 9.44 (s, 1H), 9.07 (s, 1H), 8.68 (br d, J = 12.8 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 1.7 Hz, 1H), 7.80-7.82 (m, 1H), 2.10-2.15 (m, 2H), 1.60 (br t, J = 12.7 Hz, 2H), 1.49 (s, 6H), 1.41 (s, 6H); 3Hs not observed (2 NHs, 1CH obscured by solvent peak) 307 MS m/z 431.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.85 (d, J = 1.8 Hz, 1H), 8.80 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.15 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 0.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 4.15 (s, 3H), 3.80-4.03 (m, 2H), 3.55-3.72 (m, 2H), 3.36- 3.43 (m, 1H), 2.94-3.03 (m, 1H), 2.28-2.43 (m, 1H), 1.86- 1.99 (m, 1H), 1.14 (t, J = 5.8 Hz, 6H); 2Hs not observed (NH and OH) 314 MS m/z 406.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.54 (s, 1H), 9.24 (d, J = 5.3 Hz, 1H), 9.06 (s, 1H), 8.52 (br s, 1H), 8.06 (dd, J = 5.3, 2.1 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.48 (br d, J = 8.1 Hz, 1H), 7.44 (s, 1H), 4.52 (br s, 1H), 2.19-2.29 (m, 2H), 1.67 (br t, J = 13.0 Hz, 2H), 1.61 (s, 6H), 1.50 (s, 6H); 2Hs not observed (NH and OH) 320 MS m/z 354.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.05 (s, 1H), 7.99 (d, J = 8 Hz, 1H), 7.73 (s, 1H), 7.66 (d, J = 8 Hz, 1H), 4.44 (s, 3H), 3.75-4.00 (m, 4H), 3.65-3.75 (m, 1H), 2.67 (s, 3H), 2.40-2.48 (m, 1H), 2.31 (m, 1H); 2Hs not observed (NH and OH) 321 MS m/z 459.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.87 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 7.73 (d, J = 8 Hz, 1H), 7.35 (d, J = 8 Hz, 1H), 7.30 (s, 1H), 6.01 (s, 1H), 4.33 (m, 1H), 4.16 (s, 3H), 2.25 (t, J = 16 Hz, 2H), 1.7-1.82 (m, 2H), 1.62 (d, J = 8.5 Hz, 6H), 1.53 (d, J = 5.5 Hz, 6H); 2Hs not observed (NH and OH) 344 MS m/z 484.2 [M + H]⁺; ¹H NMR (methanol-d₄), δ: 9.15 (s, 1H), 8.39 (d, J = 1.2 Hz, 1H), 8.38 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.70- 7.72 (m, 2H), 5.40-5.42 (m, 1H), 3.24 (s, 3H), 1.97-2.05 (m, 4H), 1.66 (s, 6H), 1.54 (s, 6H); 2Hs not observed (OH and NH) 351 MS m/z 488.3 [M + H]⁺; ¹H NMR (methanol-d₄), δ: 9.17 (s, 1H), 8.54 (br s, 2H), 8.25 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.71-7.74 (m, 2H), 5.39-5.43 (m, 1H), 4.46 (s, 2H), 3.25 (s, 3H), 2.01 (d, J = 7.6 Hz, 4H), 1.65 (s, 6H), 1.54 (s, 6H); 2Hs not observed (OH and NH) 359 MS m/z 445.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.48 (s, 1H), 8.87 (d, J = 4.0 Hz, 1H), 8.48 (s, 1H), 8.24- 8.40 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.27-7.39 (m, 2H), 5.96 (s, 1H), 4.29-4.49 (m, 1H), 2.15 (dd, J = 22.0, 13.7 Hz, 2H), 1.63-1.81 (m, 2H), 1.56 (d, J = 8.9 Hz, 6H), 1.46 (d, J = 5.2 Hz, 6H); 3Hs not observed (2NHs and OH) 360 MS m/z 444.7 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.85 (d, J = 6.1 Hz, 1H), 8.71 (s, 1H), 8.02-8.11 (m, 1H), 7.95-8.00 (m, 1H), 7.83-7.92 (m, 1H), 7.52-7.61 (m, 3H), 5.80-6.24 (m, 1H), 4.24-4.57 (m, 1H), 2.28 (dd, J = 19.5, 15.0 Hz, 2H), 1.68-1.89 (m, 2H), 1.65 (d, J = 8.2 Hz, 6H), 1.56 (d, J = 5.2 Hz, 6H); 3Hs not observed (2NHs and OH) 365 MS m/z 414.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.12 (s, 1H), 8.00 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.26 (d, J = 7.5 Hz, 1H), 4.30-4.19 (m, 2H), 4.00-3.95 (m, 1H), 3.77-3.73 (m, 2H), 2.67-2.61 (m, 1H), 2.32-2.24 (m, 1H), 1.49 (s, 9H); 3Hs not observed (2NHs and OH) 366 MS m/z 405.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.14 (s, 1H), 8.20 (s, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.34 (br s, 2H), 4.31-4.20 (m, 2H), 4.01-3.96 (m, 1H), 3.79-3.73 (m, 2H), 2.68-2.62 (m, 1H), 2.32-2.24 (m, 1H), 1.49 (s, 9H); 3Hs not observed (2NHs and OH) 374 MS m/z 398.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.50 (s, 1H), 8.24 (d, J = 10.2 Hz, 1H), 7.99 (s, 1H), 7.21 (m, 2H), 3.96-4.04 (m, 1H), 3.77-3.88 (m, 2H), 3.62 (br d, J = 7.6 Hz, 1H), 3.44-3.50 (m, 1H), 2.39-2.52 (m, 1H), 1.93-2.10 (m, 1H), 1.27 (s, 9H); 3Hs not observed (2 NHs and OH) 375 MS m/z 394.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.01 (br s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.12 (s, 1H), 5.99 (s, 1H), 4.41- 4.33 (m, 1H), 4.22-4.18 (m, 1H), 4.02-3.91 (m, 2H), 3.80- 3.76 (m, 1H), 2.73-2.66 (m, 1H), 2.53 (s, 3H), 2.50- 2.46 (m, 1H), 1.54 (s, 9H); 3Hs not observed (2NHs and OH) 383 MS m/z 476.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.10 (s, 1H), 8.27 (d, J = 3.4 Hz, 1H), 7.84-8.02 (m, 2H), 7.55 (dd, J = 12.6, 0.9 Hz, 1H), 7.28-7.38 (m, 2H), 5.10-5.32 (m, 1H), 3.11 (s, 3H), 1.77-1.94 (m, 2H), 1.66-1.77 (m, 2H), 1.43 (s, 6H), 1.34 (s, 6H); 3Hs not observed (OH and 2 NHs)

Example 5 Preparation of Compound 63

Step 1.

Tris(dibenzylideneacetone)dipalladium(0) (4.5 mg, 0.005 mmol) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (6.0 mg, 0.0125 mmol) were suspended in 5:1 toluene/dioxane (1 mL). The purple solution was sparged with argon for 5 minutes, then heated to 120° C. for 5 minutes. The solution was cooled to room temperature and 3-(methoxymethoxy)-4-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)phenyl trifluoromethanesulfonate (53 mg, 0.10 mmol), K₃PO₄ (64 mg, 0.30 mmol), and 1,2,3-triazole (9.0 mg, 0.013 mmol) were added. The suspension was sparged once more with argon, then heated to 120° C. for 1 h until complete consumption of aryl triflate or chloride occurred, as monitored by UPLC. The reaction was cooled to room temperature and the product was purified by chromatography on silica gel (ISCO), eluting with 5-30% MeOH in CH₂Cl₂ to afford 6-(2-(methoxymethoxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (34 mg, 75% yield) as a dark solid. MS m/z 453.6 [M+H]⁺.

Alternatively, 6-(4-chloro-2-(methoxymethoxy)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine could be used as a starting material for step 1.

Step 2.

6-(2-(methoxymethoxy)-4-(2H-1,2,3-triazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (34 mg, 0.075 mmol) was suspended in MeOH (1 mL), then HCl (4 M in dioxane, 1 mL) was added. The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated, and the product was purified by chromatography on silica gel (ISCO), eluting with 530 MeOH in CH₂Cl₂ to afford 2-(3-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)-5-(2H-1,2,3-triazol-2-yl)phenol (25 mg, 8000 yield) as an orange solid.

MS m/z 409.5 [M+H]; ¹H NMR (DMSO-d₆) δ: 9.03-9.15 (m, 2H), 8.16 (s, 2H), 7.99-8.13 (s, 2H), 7.72 (d, J=2.1 Hz, 1H), 7.64 (dd, J=8.5, 2.1 Hz, 1H), 5.14-5.32 (m, 1H), 3.13 (s, 3H), 1.98-2.04 (4, 2H), 1.80-1.85 (m, 2H), 1.52 (s, 6H), 1.48 (s, 6H).

Using the procedure described for Example 5, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 51 MS m/z 423.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.12 (s, 1H), 9.02 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.38-7.47 (m, 2H), 5.35-5.45 (m, 1H), 3.24 (s, 3H), 2.47 (s, 3H), 1.96-2.04 (m, 4H), 1.64 (s, 6H), 1.53 (s, 6H); 2Hs not observed (OH and NH) 55 MS m/z 438.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.24 (s, 1H), 8.02 (s, 1H), 8.05 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.71-7.78 (m, 1H), 7.49-7.57 (m, 2H), 7.32- 7.42 (m, 4H), 5.99 (s, 1H), 5.36-5.46 (m, 1H), 4.41-4.52 (m, 1H), 3.85 (s, 6H), 3.25 (s, 3H), 3.16 (s, 3H), 1.98- 2.19 (m, 8H); 1.56-1.70 (m, 24H); 2 rotamers (1:1), 2Hs not observed (NHs) 59 MS m/z 442.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.10 (s, 1H), 8.30 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.24 (s, 1H), 5.13-5.28 (m, 1H), 3.11 (s, 3H), 1.85-2.06 (m, 2H), 1.70- 1.81 (m, 2H), 1.46 (s, 6H), 1.42 (s, 6H); 2Hs not observed (NH and OH) 68 MS m/z 450.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.42 (br s, 1H), 9.24 (s, 1H), 9.08-9.15 (m, 2H), 8.21 (s, 1H), 8.05-8.13 (m, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H), 7.55 (dd, J = 8.5, 2.1 Hz, 1H), 5.16-5.29 (m, 1H), 3.90 (s, 3H), 3.13 (s, 3H), 2.01 (t, J = 13.0 Hz, 2H), 1.75-1.86 (m, 2H), 1.52 (s, 6H), 1.48 (s, 6H) 69 MS m/z 423.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.17 (br s, 1H), 9.04-9.13 (m, 1H), 9.02 (s, 1H), 8.01- 8.09 (m, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.92 (s, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.57 (dd, J = 8.5, 2.1 Hz, 1H), 5.13-5.31 (m, 1H), 3.13 (s, 3H), 2.38 (s, 3H), 1.95-2.05 (m, 2H), 1.80-1.86 (m, 2H), 1.52 (s, 6H), 1.48 (s, 6H) 79 MS m/z 409.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.35 (s, 1H), 9.15-9.18 (m, 1H), 9.06 (s, 1H), 8.27 (s, 1H), 8.08-8.17 (m, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.47- 7.55 (m, 2H), 5.16-5.30 (m, 1H), 3.13 (s, 3H), 2.03 (t, J = 13.0 Hz, 2H), 1.77-1.85 (m, 2H), 1.52 (s, 6H), 1.49 (s, 6H) 89 MS m/z 408.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.12 (s, 1H), 8.23 (s, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.21 (s, 2H), 5.39-5.43 (m, 1H), 3.24 (s, 3H), 2.00-2.01 (m, 4H), 1.65 (s, 6H), 1.54 (s, 6H); 2Hs not observed (NH and OH) 90 MS m/z 424.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.27-9.38 (m, 1H), 9.06 (s, 1H), 8.18-8.31 (m, 1H), 7.87-7.96 (m, 2H), 7.38-7.44 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 3.12 (s, 3H), 2.05 (t, J = 13.0 Hz, 2H), 1.72-1.83 (m, 2H), 1.52 (s, 6H), 1.50 (s, 6H); 1H not observed 93 MS m/z 426.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ 9.13-9.27 (m, 1H), 9.06 (s, 1H), 8.73 (d, J = 4.3 Hz, 1H), 8.09-8.20 (m, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 4.0 Hz, 1H), 7.49 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 5.18-5.26 (m, 1H), 3.12 (s, 3H), 2.03 (t, J = 13.0 Hz, 2H), 1.74-1.85 (m, 2H), 1.52 (s, 6H), 1.49 (s, 6H) 94 MS m/z 422.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.10-9.21 (m, 1H), 9.06 (s, 1H), 8.28 (s, 1H), 8.06-8.17 (m, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 5.16-5.29 (m, 1H), 3.12 (s, 3H), 2.11 (s, 3H), 2.02 (t, J = 13.0 Hz, 2H), 1.77- 1.84 (m, 2H), 1.52 (s, 6H), 1.48 (s, 6H) 99 MS m/z 454.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.15-9.26 (m, 1H), 9.05 (s, 1H), 9.03 (s, 1H), 8.12-8.21 (m, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.69 (dd, J = 8.5, 2.1 Hz, 1H), 5.17-5.32 (m, 1H), 3.14 (s, 3H), 1.98-2.09 (m, 2H), 1.76-1.85 (m, 2H), 1.52 (s, 6H), 1.49 (s, 6H) 119 MS m/z 424.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.11-9.23 (m, 1H), 9.03 (s, 1H), 8.10-8.20 (m, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 8.5, 2.1 Hz, 1H), 5.16-5.33 (m, 1H), 3.14 (s, 3H), 2.61 (s, 3H), 2.03 (t, J = 12.8 Hz, 2H), 1.76-1.87 (m, 2H), 1.52 (s, 6H), 1.49 (s, 6H) 121 MS m/z 395.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.33 (br s, 1H), 9.35 (br s, 1H), 8.97 (s, 1H), 8.15 (s, 2H), 8.07 (br s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 1.5 Hz, 1H), 7.62 (dd, J = 8.5, 2.0 Hz, 1H), 4.40 (br s, 1H), 2.06 (d, J = 12.5 Hz, 2H), 1.63 (t, J = 12.5 Hz, 2H), 1.50 (s, 6H), 1.45 (s, 6H) 122 MS m/z 396.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.18 (s, 1H), 9.24 (s, 1H), 9.18-9.13 (m, 1H), 8.37-8.30 (m, 1H), 8.17 (s, 2H), 8.03 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 8.5, 2.0 Hz, 1H), 5.66-5.61 (m, 1H), 2.35 (dd, J = 13.0, 3.0 Hz, 2H), 1.86 (t, J = 12.5 Hz, 2H), 1.52 (s, 6H), 1.51 (s, 6H) 133 MS m/z 443.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.40 (s, 1H), 9.15-9.23 (m, 1H), 9.05 (s, 1H), 8.10-8.18 (m, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.43-7.49 (m, 2H), 5.18-5.29 (m, 1H), 3.13 (s, 3H), 2.03 (t, J = 12.8 Hz, 2H), 1.78-1.84 (m, 2H), 1.52 (s, 6H), 1.49 (s, 6H) 135 MS m/z 433.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.42 (s, 1H), 9.17 (s, 1H), 8.44 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.40-7.47 (m, 1H), 5.20-5.36 (m, 1H), 3.16 (s, 3H), 1.64-1.72 (m, 2H), 1.51-1.58 (m, 2H), 1.32 (s, 6H), 1.18 (s, 6H); 2Hs not observed (OH and NH) 139 MS m/z 433.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.20 (s, 1H), 8.87 (s, 1H), 8.65 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.32-7.42 (m, 2H), 5.22-5.40 (m, 1H), 3.18 (s, 3H), 1.52-1.69 (m, 4H), 1.34 (s, 6H), 1.20 (s, 6H); 2Hs not observed (OH and NH) 140 MS m/z 450.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.40 (s, 1H), 9.14-9.23 (m, 1H), 9.05 (s, 1H), 8.09-8.21 (m, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.41-7.51 (m, 2H), 5.17-5.31 (m, 1H), 3.17 (s, 3H), 3.13 (s, 3H), 2.03 (t, J = 12.8 Hz, 2H), 1.75-1.86 (m, 2H), 1.52 (s, 6H), 1.49 (s, 6H); 1H not observed (OH or NH) 161 MS m/z 438.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.31-9.44 (m, 1H), 9.06 (s, 1H), 8.38 (s, 1H), 8.24-8.34 (m, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.49 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 5.16-5.30 (m, 1H), 4.45 (s, 2H), 3.12 (s, 3H), 2.07 (t, J = 12.8 Hz, 2H), 1.72-1.84 (m, 2H), 1.52 (s, 6H), 1.51 (s, 6H); 1H not observed (OH) 172 MS m/z 439.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.02 (s, 1H), 8.04 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.65 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 5.45 (t, J = 5.5 Hz, 1H), 5.15-5.29 (m, 1H), 4.66 (d, J = 5.8 Hz, 2H), 3.12 (s, 3H), 1.67-1.89 (m, 4H), 1.43 (s, 6H), 1.33 (s, 6H); 2Hs not observed (OH and NH) 187 MS m/z 380.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.38 (br s, 1H), 9.16 (s, 1H), 8.11 (d, J = 9.0 Hz, 1H), 8.07 (s, 1H), 7.73 (s, 1H), 7.35-7.33 (m, 2H), 4.31-4.22 (m, 2H), 4.02-3.98 (m, 1H), 3.80-3.75 (m, 2H), 2.68-2.62 (m, 1H), 2.33-2.25 (m, 1H), 1.49 (s, 9H); 2Hs not observed (NH and OH) 197 MS m/z 394.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.37 (s, 1H), 9.16 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.32-7.30 (m, 2H), 4.31-4.22 (m, 2H), 4.02- 3.98 (m,1H), 3.81-3.75 (m, 2H), 2.68-2.62 (m, 1H), 2.45 (s, 3H), 2.33-2.26 (m, 1H), 1.49 (s, 9H); 2Hs not observed (NH and OH) 204 MS m/z 381.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.37 (br s, 1H), 9.02 (s, 1H), 8.15 (s, 2H), 8.00 (d, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 3.92- 4.02 (m, 2H), 3.72-3.85 (m, 2H), 3.50-3.62 (m, 3H), 1.24 (s, 9H); 1 H not observed (OH or NH) 218 MS m/z 339.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.03 (s, 1H), 8.14 (s, 2H), 7.99 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 3.75-3.98 (m, 4H), 3.62- 3.70 (br s, 1H), 2.66 (s, 3H), 2.40-2.48 (m, 1H), 2.25-2.35 (m, 1H); 2Hs not observed (NH and OH) 219 MS m/z 356.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.05 (s, 1H), 8.69 (d, J = 4 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 4 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 3.70-4.00 (m, 4H), 3.60-3.70 (m, 1H), 2.66 (s, 3H), 2.40-2.50 (m, 1H), 2.25-2.35 (m, 1H); 2Hs not observed (NH and OH) 220 MS m/z 338.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.76 (s, 1H), 9.10 (s, 1H), 8.31 (s, 1H), 8.08 (d, J = 5 Hz, 1H), 7.95 (s, 1H), 7.42 (m, 2H), 3.80-4.00 (m, 4H), 3.72 (m, 1H), 2.65 (s, 3H), 2.43 (m, 1H), 2.31 (m, 1H); 2Hs not observed (NH and OH) 228 MS m/z 392.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.42 (s, 1H), 7.85 (s, 2H), 7.34-7.31 (m, 2H), 5.98 (s, 1H), 4.27 (s, 2H), 4.16 (s, 2H), 3.53 (d, J = 12.8 Hz, 3H), 3.20- 3.12 (m, 2H), 2.91 (s, 3H), 2.45 (s, 3H), 2.37 (d, J = 14.5 Hz, 2H), 2.13 (t, J = 11.9 Hz, 2H); 1H not observed (OH) 229 MS m/z 396.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.34 (d, J = 4.4 Hz, 1H), 7.73-7.64 (m, 2H), 7.41-7.33 (m, 2H), 5.94 (s, 1H), 4.26 (s, 2H), 4.14 (s, 2H), 3.53 (d, J = 12.7 Hz, 2H), 3.14 (t, J = 12.7 Hz, 2H), 2.90 (s, 3H), 2.37 (d, J = 14.6 Hz, 2H), 2.13 (t, J = 13.8 Hz, 2H); 1H not observed (OH) 230 MS m/z 396.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.13 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 9.1 Hz, 1H), 7.20 (s, 1H), 5.95 (s, 1H), 4.26 (s, 2H), 4.15 (s, 2H), 3.53 (d, J = 12.4 Hz, 2H), 3.15 (t, J = 12.6 Hz, 2H), 2.90 (s, 3H), 2.37 (d, J = 14.4 Hz, 2H), 2.13 (t, J = 13.8 Hz, 2H); 1H not observed (OH) 231 MS m/z 378.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.57 (s, 1H), 8.14 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.37 (d, J = 8.9 Hz, 2H), 5.99 (s, 1H), 4.28 (s, 2H), 4.16 (s, 2H), 3.53 (d, J = 12.7 Hz, 2H), 3.15 (t, J = 12.6 Hz, 2H), 2.90 (s, 3H), 2.37 (d, J = 14.3 Hz, 2H), 2.14 (t, J = 13.6 Hz, 2H); 1H not observed (OH) 232 MS m/z 379.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.06 (s, 1H), 8.00-7.90 (m, 3H), 7.73-7.65 (m, 2H), 4.09 (br d, J = 20.9 Hz, 4H), 3.51 (br s, 2H), 3.11 (br s, 2H), 2.90 (s, 3H), 2.30 (br s, 2H), 2.08 (br s, 2H); 1H not observed (OH) 238 MS m/z 381.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.37 (br s, 1H), 9.02 (s, 1H), 8.15 (s, 2H), 8.00 (d, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 3.92- 4.02 (m, 2H), 3.72-3.85 (m, 2H), 3.50-3.62 (m, 3H), 1.24 (s, 9H); 1H not observed (OH or NH) 239 MS m/z 426.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 10.06-10.18 (m, 1H), 9.66 (s, 1H), 9.08 (s, 1H), 8.36 (br s, 1H), 8.13 (d, J = 13.4 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 7.39 (s, 1H), 7.36 (d, J = 8.2 Hz, 1H), 4.74-4.84 (m, 2H), 2.38 (s, 3H), 1.96-2.07 (m, 1H), 1.84-1.93 (m, 1H), 1.57 (d, J = 18.5 Hz, 6H), 1.49 (d, J = 5.8 Hz, 6H) 240 MS m/z 430.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.94 (br s, 1H), 9.10 (s, 1H), 8.33 (br s, 1H), 8.13 (d, J = 13.1 Hz, 1H), 8.07 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 6.77-7.37 (m, 3H), 4.76-4.85 (m, 2H), 1.95-2.07 (m, 1H), 1.85-1.94 (m, 1H), 1.57 (d, J = 18.5 Hz, 6H), 1.48 (d, J = 6.1 Hz, 6H) 264 MS m/z 367.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.06 (s, 1H), 7.87-7.98 (m, 3H), 7.59-7.68 (m, 2H), 3.96 (dd, J = 11.0, 7.0 Hz, 1H), 3.76-3.91 (m, 1H), 3.54-3.70 (m, 2H), 3.38 (br dd, J = 11.1, 6.6 Hz, 1H), 2.98 (dt, J = 12.5, 6.3 Hz, 1H), 2.29-2.39 (m, 1H), 1.86-1.97 (m, 1H), 1.14 (t, J = 6.1 Hz, 6H); 2Hs not observed (NH and OH) 273 MS m/z 394.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.58 (s, 1H), 8.15 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.81 (s, 1H), 7.41-7.36 (m, 2H), 6.01 (s, 1H), 4.49-4.40 (m, 1H), 2.31-2.18 (m, 2H), 1.87-1.74 (m, 2H), 1.65 (s, 3H), 1.63 (s, 3H), 1.55 (s, 3H), 1.54 (s, 3H); 3Hs not observed (2 NHs and OH) 274 MS m/z 408.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.44 (s, 1H), 7.89-7.83 (m, 2H), 7.36-7.31 (m, 2H), 6.00 (s, 1H), 4.48-4.38 (m, 1H), 2.28-2.19 (m, 2H), 1.86-1.75 (m, 2H), 1.64 (s, 3H), 1.63 (s, 3H), 1.55 (s, 3H), 1.54 (s, 3H); 3Hs not observed (2NHs and OH) 275 MS m/z 412.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 7.99 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.35 (d, J = 9.5 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.19 (s, 1H), 5.98 (s, 1H), 4.37 (m, 1H), 2.29-2.18 (m, 2H), 1.78 (m, 2H), 1.63 (s, 3H), 1.61 (s, 3H), 1.55 (s, 3H), 1.53 (s, 3H); 2Hs not observed (NH and OH) 276 MS m/z 412.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.35 (d, J = 4.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 4.0 Hz, 1H), 7.40-7.35 (m, 2H), 5.97 (s, 1H), 4.41-4.30 (m, 1H), 2.31-2.19 (m, 2H), 1.84-1.72 (m, 2H), 1.63 (s, 3H), 1.61 (s, 3H), 1.55 (s, 3H), 1.53 (s, 3H); 3Hs not observed (2NHs and OH 315 MS m/z 420.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.00 (s, 1H), 8.47 (s, 2H), 8.37 (d, J = 2.6 Hz, 1H), 8.07 (d, J = 4.6 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 8.4, 4.9 Hz, 1H), 6.73 (dd, J = 8.5, 2.1 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 4.54 (br s, 1H), 2.29 (br dd, J = 13.9, 3.4 Hz, 2H), 1.62-1.66 (m, 2H), 1.61 (s, 6H), 1.49 (s, 6H) 324 MS m/z 413.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.08 (s, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.93-7.97 (m, 2H), 7.69-7.75 (m, 2H), 4.71-4.83 (m, 1H), 4.42-4.65 (m, 1H), 1.74-1.86 (m, 2H), 1.41 (m, 6H), 1.28-1.31 (m, 6H); 3Hs not observed (2NHs and OH) 326 MS m/z 380.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.08 (s, 1H), 8.07 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.15 (d, J = 9.0 Hz, 1H), 7.13 (s, 1H), 4.06 (dd, J = 11.0, 6.5 Hz, 1H), 3.97-3.88 (m, 2H), 3.73-3.70 (m, 1H), 3.60 (dd, J = 11.5, 6.0 Hz, 1H), 3.29-3.25 (m, 1H), 2.51-2.42 (m, 1H), 2.26 (s, 3H), 2.15- 2.06 (m, 1H), 1.28 (t, J = 5.0 Hz, 6H); 2Hs not observed (NH and OH) 331 MS m/z 366.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.16 (s, 1H), 8.75 (br s, 1H), 8.07 (br d, J = 8.5 Hz, 1H), 7.85 (br s, 1H), 7.44 (br s, 1H), 7.23-7.35 (m, 2H), 4.13-4.32 (m, 2H), 3.97-4.08 (m, 1H), 3.76-3.91 (m, 2H), 3.48-3.70 (m, 1H), 2.58-2.69 (m, 1H), 2.24-2.40 (m, 1H), 1.46 (t, J = 4.6 Hz, 6H); 2Hs not observed (NH and OH) 338 MS m/z 384.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.13 (s, 1H), 8.33 (dd, J = 15.0, 4.0 Hz, 1H), 7.85 (dd, J = 111.5, 8.5 Hz, 1H), 7.68 (dd, J = 9.0, 3.5 Hz, 1H), 7.39-7.35 (m, 2H), 4.31-4.22 (m, 1H), 4.18-4.10 (m, 1H), 4.00-3.75 (m, 3H), 3.60-3.51 (m, 1H), 2.67-2.58 (m, 1H), 2.48-2.29 (m, 1H), 1.44 (t, J = 6.0 Hz, 6H); 2Hs not observed (NH and OH) 381 MS m/z 459.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.42 (s, 1H), 9.04 (s, 1H), 8.57 (s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.30 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.93 (dd, J = 5.5, 1.1 Hz, 1H), 7.47-7.55 (m, 2H), 5.20-5.27 (m, 1H), 3.11 (s, 3H), 1.57-1.71 (m, 4H), 1.33 (s, 6H), 1.21 (s, 6H); 1H not observed (OH or NH) 417 MS m/z 407.5 [M + H]⁺; ¹H NMR (methanol-d₄): 9.13 (s, 1H), 8.01 (d, J = 9.00 Hz, 1H), 7.96 (s, 2H), 7.73 (s, 2H), 5.41-5.30 (m, 1H), 3.22 (s, 3H), 2.37-2.31 (m, 2H), 2.15-2.01 (m, 6H), 1.57 (s, 6H); 2Hs not observed (NH and OH)

Example 6 Preparation of Compound 13

Step 1

A dry screw cap vial was equipped with a magnetic stir bar and charged with 6-bromo-3-(methylthio)-1,2,4-triazine (0.2 g, 0.9 mmol, 1.0 equiv), 4-(3-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (0.4 g, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dicholoropalladium(II) (0.08 g, 0.1 mmol), and K₂CO₃ (0.4 g, 2.6 mmol) and was purged with argon. Dioxane (4 mL) and water (1 mL) were added, and the reaction was stirred at 90° C. for 1 h. The crude mixture was partitioned between water and EtOAc, washed with water, and the organic layer was dried over MgSO₄, filtered, and concentrated. The crude oil was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (0-75% EtOAc) to afford 6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3-(methylthio)-1,2,4-triazine (0.2 g, 61% yield) as a yellow solid. MS m/z 414.2 [M+H]⁺.

Step 2:

To a solution of 6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3-(methylthio)-1,2,4-triazine (0.7 g, 1.7 mmol) in CH₂Cl₂ (15 mL) was added 3-chlorobenzoperoxoic acid (0.6 g, 3.4 mmol). The reaction mixture was stirred at 22° C. for 2 h. The crude mixture was purified by silica gel chromatography eluting with a EtOAc/hexanes gradient (0-100% EtOAc) to afford 6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3-(methylsulfonyl)-1,2,4-triazine (0.6 g, 1.3 mmol, 78%) as yellow solid. MS m/z 446.2 [M+H]⁺.

Step 3

A vial was equipped with a magnetic stir bar and charged with 6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-3-(methylsulfonyl)-1,2,4-triazine (0.06 g, 0.13 mmol), 2,2,6,6-tetramethylpiperidin-4-amine (0.03 g, 0.18 mmol), and dichloroethane (5 mL) and the reaction was stirred at room temperature for 48 h. The solvents were removed, and the crude solid was purified by silica gel chromatography, eluting with a MeOH/CH₂Cl₂ gradient (0-15% MeOH, containing 2.5% NH₄OH) to afford 6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (0.03 g, 36% yield) as yellow solid. MS m/z 522.3 [M+H]⁺.

Step 4

To a solution of 6-(2-(methoxymethoxy)-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-3-amine (0.03 g, 0.05 mmol) in MeOH (1 mL) was added 4.0M HCl in dioxane (1 mL), and the mixture was stirred for 1 h at room temperature. The solvents were removed, and the crude residue was purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0-15% MeOH, containing 2.5% NH₄OH) to afford 5-(1H-pyrazol-4-yl)-2-(3-((2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,2,4-triazin-6-yl)phenol hydrochloride (0.02 g, 72% yield) as a yellow solid.

MS m/z 394.3 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 9.07 (s, 1H), 8.08 (br s, 1H), 7.96 (br s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.24, (dd, J=8.0, 1.5 Hz, 1H), 7.21 (d, J=2.0 Hz, 1H), 4.58 (t, J=12.5 Hz, 1H), 2.30 (dd, J=13.5, 2.5 Hz, 2H), 1.66-1.60 (m, 2H), 1.62 (s, 6H), 1.50 (s, 6H); 4 Hs not observed (3NHs and OH).

Using the procedure described for Example 6, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 11 MS m/z 395.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 13.06 (br s, 1H), 10.96 (br s, 1H), 9.29 (s, 1H), 8.24 (br s, 1H), 7.94 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.0, 1.5 Hz, 1H), 7.25 (d, J = 1.5 Hz, 1H), 5.61 (t, J = 10.0 Hz, 1H), 2.27 (br s, 2H), 1.01-1.97 (m, 14H); 1H not observed (NH or OH) 19 MS m/z 352.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.10 (s, 1H), 8.02 (br. s, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.0, 1.5 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 4.98 (dt, J = 12.0, 4.0 Hz, 1H), 3.59 (d, J = 13.0 Hz, 2H), 3.26 (d, J = 3.5 Hz, 1H), 3.24 (s, 3H), 3.21 (d, J = 2.5 Hz, 1H), 2.22 (dd, J = 13.0, 3.5 Hz, 2H), 2.07 (d, J = 3.0 Hz, 2H); 3Hs not observed (2NHs and OH). 20 MS m/z 352.2 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.13 (s, 1H), 8.02 (br. s, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 4.22 (dd, J = 15.5, 8.5 Hz, 1H), 4.01-3.95 (m, 1H), 3.92 (dd, J = 15.0, 3.5 Hz, 1H), 3.45 (dd, J = 18.5, 8.0 Hz, 1H), 3.39 (s, 3H), 2.34-2.28 (m, 1H), 2.22-2.01 (m, 3H), 1.87 (dd, J = 13.0, 9.5 Hz, 1H); 3Hs not observed (2NHs and OH). 21 MS m/z 378.3 [M + H]⁺; ¹H NMR (methanol-d₄): 9.09 (s, 1H), 8.01 (br. s, 2H), 7.83 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 8.0, 1.5 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H), 5.36-5.29 (m, 1H), 4.20 (br. s, 2H), 3.19 (s, 3H), 2.28 (dt, J = 3.5, 15 Hz, 4H), 2.23 (br. s, 4H), 2.0- 1.94 (m, 2H); 1H not observed (NH or OH). 22 MS m/z 392.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.10 (s, 1H), 8.02 (br. s, 2H), 7.84 (d, J = 10 Hz, 1H), 7.24 (dd, J = 8.0, 1.5 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 5.98-5.92 (m, 1H), 3.88 (br. s, 2H), 3.18 (s, 3H), 2.46 (dt, J = 3.6, 14 Hz, 2H), 2.31-2.16 (m, 4H), 2.13-2.06 (m, 4H), 1.92-1.89 (m, 2H); 1H not observed (NH or OH). 52 MS m/z 352.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.07 (s, 1H), 8.01 (s, 2H), 7.83 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 8.5, 2.0 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 4.18-4.22 (m, 1H), 3.52-3.56 (m, 2H), 3.19-3.27 (m, 2H), 2.91 (s, 3H), 2.34-2.36 (m, 2H), 1.92-2.00 (m, 2H); 3Hs not observed (2NHs and OH) 67 MS m/z 426.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.19 (s, 1H), 8.52-8.06 (m, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 8.3 Hz, 2H), 7.24 (s, 1H), 5.60 (dd, J = 33.5, 13.3 Hz, 1H), 3.34 (s, 3H), 2.52 (t, J = 13.5 Hz, 1H), 2.02 (d, J = 12.5 Hz, 1H), 1.72 (s, 3H), 1.68 (s, 3H), 1.62 (s, 3H), 1.58 (s, 3H), 0.94-0.86 (m, 1H); 3Hs not observed (2 NHs and OH) 82 MS m/z 367.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.31 (s, 1H), 8.09 (br s, 1H), 7.94 (br s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 9.5 Hz, 1H), 7.22 (s, 1H), 5.40- 5.46 (m, 1H), 3.44-3.49 (m, 2H), 2.58-2.61 (m, 2H), 1.68 (q, J = 12.5 Hz, 2H), 1.43 (s, 3H), 1.42 (s, 3H); 3Hs not observed (2 NHs and OH) 95 MS m/z 364.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.06 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.25-7.19 (m, 3H), 4.00-3.93 (m, 6H), 3.70-3.65 (m, 2H), 2.15-2.09 (m, 2H), 2.00 (t, J = 5.7 Hz, 2H); 3Hs not observed (2NHs and OH) 96 MS m/z 364.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.08 (s, 2H), 7.59 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.21 (s, 1H), 5.94 (s, 1H), 4.19 (s, 4H), 3.26 (t, J = 5.0 Hz, 4H), 2.19 (t, J = 5.0 Hz, 4H); 3Hs not observed (2NHs and OH) 100 MS m/z 336.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 8.27-8.19 (br s, 1H), 7.98-7.92 (br s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 8.0, 2.0 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 3.88-3.82 (m, 2H), 3.68-3.62 (m, 2H), 2.64 (t, J = 2.0 Hz, 1H), 1.93 (s, 2H); 3Hs not observed (2NHs and OH) 109 MS m/z 364.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.33 (br s, 1H), 9.07 (s, 1H), 8.20 (br s, 1H), 7.95 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.23-7.20 (m, 2H), 3.98 (d, J = 9.0 Hz, 2H), 3.84 (d, J = 8.5, 2H), 3.01 (s, 2H), 2.75 (s, 2H), 1.81 (t, J = 5.0 Hz, 2H), 1.55 (t, J = 5.0 Hz, 2H); 2 H not observed (2 NHs) 110 MS m/z 350.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.14 (br s, 1H), 9.10 (s, 1H), 8.95 (br s, 1H), 8.08 (s, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.23-7.20 (m, 2H), 4.08- 4.05 (m, 2H), 3.97-3.94 (m, 2H), 3.86 (br s, 2H), 3.64 (br s, 2H), 2.32 (t, J = 7.0 Hz, 2H); 1H not observed (NH or OH) 120 MS m/z 395.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.22 (s, 1H), 7.93 (s, 2H), 7.82 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 8.00, 1.5 Hz, 1H), 7.12 (s, 1H), 5.37- 5.30 (m, 1H), 2.64-2.61 (m, 2H), 1.83-1.75 (m, 2H), 1.63- 1.49 (m, 4H), 0.98 (t, J = 10 Hz, 6H); 3Hs not observed (2NHs and OH); 2Hs (CH₂ signal) are obscured by the solvent peak at 3.33 ppm 113 MS m/z 378.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.05 (s, 1H), 8.07 (br s, 1H), 7.92 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 8.0, 2.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 3.93-3.88 (m, 2H), 3.22-3.17 (m, 3H), 2.67 (s, 3H), 2.53 (t, J = 8.0 Hz, 2H), 2.24 (d, J = 11.0 Hz, 2H), 2.00 (td, J = 12.0, 4.0 Hz, 2H); 1H not observed (NH or OH) 114 MS m/z 338.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.12 (s, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 8.0, 2.0 Hz, 1H), 7.21 (s, 1H), 5.96 (s, 1H), 4.16-4.07 (m, 2H), 4.05-3.74 (m, 3H), 2.83 (s, 3H), 2.65-2.59 (m, 1H), 2.49-2.38 (m, 1H); 3Hs not observed (2NHs and OH) 115 MS m/z 350.2 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.25 (br s, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 5.97 (d, J = 12.5 Hz, 1H), 4.26-4.00 (m, 3H), 3.70 (dd, J = 20.0, 5.0 Hz, 1H), 3.45 (dd, J = 26.0, 10.5 Hz, 1H), 1.24 (dt, J = 10.0, 5.0 Hz, 1H), 1.09-1.04 (m, 2H), 1.00-0.95 (m, 1H); 4Hs not observed (3NHs and OH) 116 MS m/z 364.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.13 (d, J = 5.0 Hz, 1H), 8.03 (br s, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 8.0, 1.5 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H), 5.34-5.15 (m, 1H), 4.34 (dd, J = 15.0, 4.0 Hz, 1H), 4.17-3.97 (m, 2H), 3.86-3.75 (m, 1H), 3.68-3.64 (m, 1H), 3.51- 3.36 (m, 2H), 3.26-3.09 (m, 2H), 2.43-2.09 (m, 3H), 2.04-1.83 (m, 1H); 1H not observed (NH or OH) 117 MS m/z 364.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.14 (s, 1H), 8.02 (br s, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0, 1H), 7.20 (s, 1H), 4.39 (d, J = 13.5 Hz, 1H), 4.26 (t, J = 7.0 Hz, 1H), 4.03-3.75 (m, 5H), 3.49-3.45 (m, 1H), 3.07 (s, 3H), 2.67-2.59 (m, 1H), 2.02-1.95 (m, 1H); 2Hs not observed (NH and OH) 118 MS m/z 336.2 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.08 (s, 1H), 8.06 (br s, 1H), 7.92 (br s, 1H), 7.82 (d, J = 8.0, 1H), 7.22 (dd, J = 8.0, 2.0 Hz, 1H), 7.18 (d, J = 1.5 Hz, 1H), 4.46 (s, 4H), 4.35 (s, 4H); 3Hs not observed (2NHs and OH) 126 MS m/z 412.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 13.00 (br s, 1H), 11.45 (br s, 1H), 9.08 (s, 1H), 8.24 (br s, 1H), 7.95 (br s, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.20-7.25 (m, 2H), 4.30-4.70 (m, 2H), 1.64 (t, J = 13.1 Hz, 1H), 1.56 (dd, J = 12.2, 3.1 Hz, 1H), 1.33- 1.47 (m, 1H), 1.22 (br d, J = 14.0 Hz, 6H), 1.09 (br d, J = 14.0 Hz, 6H); 1H not observed (OH) 127 MS m/z 392.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.04 (s, 1H), 8.10-7.89 (m, 2H), 7.80 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 8.0, 1.5 Hz, 1H), 7.17 (d, J = 1.5 Hz, 1H), 3.94 (d, J = 11.4 Hz, 2H), 3.69 (d, J = 11.4 Hz, 2H), 2.76 (q, J = 7.2 Hz, 4H), 1.93 (s, 2H), 1.64 (s, 1H), 1.14 (t, J = 7.2 Hz, 6H); 2Hs not observed (NH and OH) 137 MS m/z 364.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 13.00 (br s, 1H), 11.42 (s, 1H), 9.10 (s, 1H), 8.35-7.92 (m, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.21 (s, 1H), 3.86 (br s, 2H), 3.76 (br s, 2H), 3.66 (s, 1H), 2.36-2.31 (m, 2H), 2.20-2.17 (m, 1H), 0.65 (br s, 4H); 1H not observed (NH or OH) 138 MS m/z 380.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.44 (s, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 5.98 (s, 1H), 4.29- 4.40 (m, 1H), 4.14-4.19 (m, 1H), 3.87-3.98 (m, 2H), 3.71-3.80 (m, 1H), 2.64-2.74 (m, 1H), 2.39-2.51 (m, 1H), 1.52 (s, 9H); 3Hs not observed (2NHs or OH) 148 MS m/z 366.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.06 (s, 1H), 7.99 (br s, 2H), 7.80 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 8.0, 1.5 Hz, 1H), 7.17 (d, J = 1.5 Hz, 1H), 4.03 (dd, J = 11.5, 6.5 Hz, 1H), 3.92-3.86 (m, 2H), 3.68-3.65 (m, 1H), 3.55 (dd, J = 11.5, 6.5 Hz, 1H), 2.47-2.41 (m, 1H), 1.26 (t, J = 5.5 Hz, 6H), 1.20-1.16 (m, 2H); 3Hs not observed (2NHs and OH) 154 MS m/z 394.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.08 (s, 1H), 8.00 (br s, 2H), 7.82 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.0, 1H), 7.19 (s, 1H), 4.13-4.09 (m, 1H), 3.99-3.90 (m, 2H), 3.69-3.63 (m, 1H), 3.57- 3.52 (m, 1H), 2.52-2.49 (m, 1H), 2.14-2.09 (m, 1H), 1.72-1.64 (m, 2H), 1.30 (s, 6H), 1.00 (t, J = 7.5 Hz, 3H); 3Hs not observed (2NHs and OH) 157 MS m/z 458.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.29 (s, br, 1H), 9.12 (s, 1H), 8.80-8.69 (m, 2H), 8.08 (s, br, 2H), 7.85 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 4.30-4.22 (m, 1H), 4.08-4.00 (m, 1H), 3.85-3.79 (m, 1H), 3.74- 3.69 (m, 1H), 3.66-3.23 (m, 12H), 2.27-2.20 (m, 1H), 2.17 (s, 1H), 1.93 (q, J = 11.6 Hz, 2H), 1.67 (q, J = 12.3 Hz, 2H) 159 MS m/z 458.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ:9.13 (s, 1H), 8.62 (br s, 2H), 8.09 (s, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 4.18-4.13 (m, 1H), 4.07-4.04 (m, 1H), 3.89-3.81 (m, 2H), 3.69-3.57 (m, 1H), 3.52 (s, 1H), 2.33-2.31 (m, 1H), 2.20 (br s, 2H), 2.04 (d, J = 14.0 Hz, 2H), 1.89-1.86 (m, 6H), 1.74 (br s, 2H), 1.64 (d, J = 12.5 Hz, 3H); 1H not observed (NH or OH) 160 MS m/z 486.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.28 (br s, 1H), 9.12 (s, 1H), 9.03-8.96 (m, 2H), 8.08 (s, 2H), 7.85 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 4.23 (br s, 1H), 4.04 (br s, 1H), 3.82-3.78 (m, 2H), 3.76-3.73 (m, 3H), 2.32-2.28 (s, 1H), 1.84-1.77 (m, 2H), 1.65-1.56 (m, 4H), 1.38-1.29 (m, 4H), 1.21-1.15 (m, 2H), 0.90 (s, 6 162 MS m/z 392.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.58 (s, 2H), 7.68 (dd, J = 8.1, 4.7 Hz, 1H), 7.38-7.54 (m, 1H), 7.29-7.36 (m, 2H), 5.97 (d, J = 4.3 Hz, 1H), 3.83-4.09 (m, 4H), 3.59-3.73 (m, 1H), 3.38-3.42 (m, 1H), 3.08-3.20 (m, 1H), 3.03 (br d, J = 2.4 Hz, 3H), 2.99 (s, 3H), 2.30-2.40 (m, 1H), 2.12-2.28 (m, 2H), 1.74-1.86 (m, 1H); 2H not observed (NH and OH) 166 MS m/z 378.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.09 (s, 1H), 7.94-8.11 (m, 2H), 7.84 (br d, J = 8.2 Hz, 1H), 7.61-7.77 (m, 1H), 7.18-7.28 (m, 2H), 3.77-3.88 (m, 2H), 3.71-3.76 (m, 1H), 3.67 (br dd, J = 10.8, 6.9 Hz, 1H), 2.96-3.07 (m, 1H), 2.74-2.94 (m, 4H), 2.72 (s, 3H), 2.61-2.66 (m, 1H), 2.02-2.14 (m, 1H), 1.81-1.91 (m, 1H); 2H not observed (NH and OH) 167 MS m/z 392.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.32 (s, 2H), 7.63 (br d, J = 7.9 Hz, 1H), 7.29 (br d, J = 8.2 Hz, 1H), 7.26 (s, 1H), 5.94 (s, 1H), 4.07 (br s, 1H), 3.71-3.91 (m, 3H), 3.55-3.64 (m, 1H), 3.13-3.31 (m, 2H), 3.01 (br s, 3H), 2.89-2.97 (m, 3H), 2.38-2.50 (m, 1H), 2.18-2.29 (m, 1H), 1.98-2.12 (m, 1H), 1.64-1.79 (m, 1H); 2Hs not observed (NH and OH) 170 MS m/z 408.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.11 (s, 1H), 8.08-7.99 (m, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0, 1H), 7.19 (s, 1H), 4.29- 4.21 (m, 2H), 4.01-3.96 (m, 1H), 3.77-3.69 (m, 2H), 2.67-2.61 (m, 1H), 2.34-2.27 (m, 1H), 1.94-1.75 (m, 4H), 1.41 (s, 3H), 1.03 (t, J = 7.5 Hz, 6H); 3Hs not observed (2 NHs and OH) 171 MS m/z 394.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.15 (s, 1H), 8.24-7.98 (br s, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 4.43-4.39 (m, 1H), 4.35-4.29 (m, 1H), 3.77-3.69 (m, 1H), 3.43 (t, J = 9.5 Hz, 1H), 2.76-2.71 (m, 1H), 1.83- 1.77 (m, 1H), 1.51 (d, J = 6.0 Hz, 3H), 1.32 (s, 9H); 3Hs not observed (2NHs and OH) 180 MS m/z 392.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.11 (br s, 2H), 7.58 (d, J = 8.2 Hz, 1H), 7.16-7.28 (m, 2H), 5.92 (s, 1H), 3.77-4.06 (m, 1H), 3.61-3.76 (m, 3H), 3.09-3.22 (m, 4H), 1.67-1.92 (m, 8H); 3Hs not observed (2 NHs and OH) 181 MS m/z 378.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.08 (br s, 2H), 7.59 (d, J = 8.2 Hz, 1H), 7.14-7.28 (m, 2H), 5.92 (s, 1H), 3.81-4.06 (m, 1H), 3.64-3.80 (m, 3H), 3.43-3.50 (m, 2H), 3.20-3.27 (m, 2H), 2.06 (q, J = 7.3 Hz, 2H), 1.81-1.94 (m, 3H), 1.74-1.79 (m, 1H); 3Hs not observed (2 NHs and OH) 182 MS m/z 406.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.65 (br s, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.31-7.38 (m, 2H), 5.96 (s, 1H), 3.80-3.88 (m, 1H), 3.66-3.78 (m, 3H), 3.61 (br d, J = 9.2 Hz, 1H), 3.53 (br d, J = 10.4 Hz, 1H), 3.16-3.22 (m, 1H), 2.89-3.01 (m, 4H), 1.95-2.18 (m, 4H), 1.84-1.95 (m, 2H), 1.73 (br s, 2H); 2Hs not observed (NH and OH) 183 MS m/z 392.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.75 (br s, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.32-7.41 (m, 2H), 5.97 (s, 1H), 3.67-3.86 (m, 5H), 3.67-3.89 (m, 1H), 3.27-3.32 (m, 1H), 3.09 (br dd, J = 11.0, 8.9 Hz, 1H), 3.00 (s, 3H), 2.25 (br d, J = 8.2 Hz, 1H), 2.07-2.19 (m, 1H), 1.97 (br s, 3H), 1.84-2.04 (m, 1H); 2Hs not observed (NH and OH) 193 MS m/z 420.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.08 (s, 1H), 8.18-7.88 (br s, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 8.5, 2.0 Hz, 1H), 7.18 (d, J = 1.5 Hz, 1H), 3.92-3.86 (m, 2H), 3.79 (d, J = 4.0 Hz, 2H), 3.71 (dd, J = 12.0, 7.5 Hz, 1H), 3.22-3.16 (m, 1H), 3.01-2.95 (m, 1H), 2.25-2.11 (m, 2H), 1.98-1.89 (m, 1H), 1.69-1.64 (m, 1H), 1.44 (s, 9H); 3Hs not observed (2NHs and OH) 199 MS m/z 408.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.03 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.10-7.22 (m, 2H), 4.45 (br t, J = 11.6 Hz, 1H), 3.96 (s, 3H), 2.03 (br d, J = 11.0 Hz, 2H), 1.35 (s, 6H), 1.24-1.31 (m, 2H), 1.22 (s, 6H); 3Hs not observed (2 NHs and OH) 201 MS m/z 426.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.05 (s, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.78 (br d, J = 7.9 Hz, 1H), 7.05-7.26 (m, 2H), 4.65-4.75 (m, 1H), 3.93 (s, 3H), 1.70-1.80 (m, 2H), 1.35 (br d, J = 6.4 Hz, 6H), 1.16-1.27 (m, 7H); 3Hs not observed (2NHs and OH) 202 MS m/z 394.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.07 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.13-7.21 (m, 2H), 3.99-4.08 (m, 2H), 3.96 (s, 3H), 3.83-3.90 (m, 1H), 3.57-3.73 (m, 2H), 2.29-2.45 (m, 1H), 1.83-2.01 (m, 1H), 1.22 (s, 9H); 2Hs not observed (NH and OH) 203 MS m/z 380.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.06 (s, 1H), 8.01 (s, 1H), 7.85 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.16 (s, 1H), 3.97- 4.01 (m, 1H), 3.96 (s, 3H), 3.77-3.94 (m, 1H), 3.57-3.77 (m, 2H), 3.40 (dd, J = 10.8, 6.9 Hz, 1H), 2.95-3.05 (m, 1H), 2.28-2.42 (m, 1H), 1.86-2.00 (m, 1H), 1.16 (br t, J = 5.8 Hz, 6H); 2Hs not observed (NH and OH) 205 MS m/z 352.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.07 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.10-7.26 (m, 2H), 3.96 (s, 3H), 3.79-3.92 (m, 2H), 3.65-3.74 (m, 1H), 3.49-3.65 (m, 1H), 3.41-3.48 (m, 1H), 2.46 (s, 3H), 2.22-2.36 (m, 1H), 1.91-2.09 (m, 1H); 2Hs not observed (NH and OH) 206 MS m/z 394.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.07 (s, 1H), 8.01, (s, 2H), 7.82 (d, J = 8.00 Hz, 1H), 7.23 (d, J = 8.00 Hz, 1H), 7.19 (s, 1H), 4.94 (d, J = 15 Hz, 2H), 3.79-3.71, (m, 1H), 3.20 (t, J = 14.50 Hz, 2H), 2.21 (d, J = 12.50 Hz, 2H), 1.78-1.67, (m, 2H), 1.46, (s, 9H); 3Hs not observed (2 NHs and OH) 212 MS m/z 394.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.09 (s, 1H), 8.01 (s, 2H), 7.82 (d, J = 8.00 Hz, 1H), 7.23 (d, J = 8.50 Hz, 1H), 7.19 (s, 1H), 4.91 (d, J = 13.50 Hz, 1H), 4.58 (d, J = 13.50 Hz, 1H), 3.67-3.65, (m, 1H), 3.55-3.52, (m, 1H), 3.46-3.38 (m, 1H), 2.29-2.21, (m, 1H), 1.97-1.75, (m, 3H), 1.48 (s, 9H); 3Hs not observed (2 NHs and OH) 226 MS m/z 392.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.25 (s, 1H), 9.29 (br s, 1H), 9.07 (s, 1H), 8.17 (s, 1H), 7.87 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 4.04 (br s, 2H), 3.97 (br s, 2H), 3.88 (s, 3H), 3.40 (m, 2H), 3.02 (m, 2H), 2.78 (s, 3H), 2.18 (m, 2H), 1.91 (m, 2H) 262 MS m/z 352.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.13 (s, 1H), 8.17 (s, 2H), 7.87 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 2.6, 4.1 Hz, 2H), 4.81 (d, J = 13.3 Hz, 2H), 3.43-3.30 (m, 2H), 3.25-3.12 (m, 2H), 1.37 (d, J = 6.4 Hz, 6H); 3Hs not observed (2 NH and OH) 278 MS m/z 398.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.97 (br s, 1H), 9.69 (br s, 1H), 9.13(s, 1H), 8.08 (s, 2H), 7.85 (d, J = 8.0 Hz, 1H), 7.25-7.22 (m, 2H), 5.79 (d, J = 53.0 Hz, 2H), 4.39-4.26 (m, 2H), 4.13-3.99 (m, 1H), 3.94-3.80 (m, 2H), 1.44 (s, 9H) 282 MS m/z 380.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.11 (s, 1H), 8.21 (s, 2H), 7.88 (d, J = 8.5 Hz, 1H), 7.30-7.22 (m, 2H), 4.00 (s, 4H), 1.48 (s, 12H); 3Hs not observed (2 NHs and OH) 297 MS m/z 380.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.30-8.62 (m, 2H), 7.68 (br d, J = 8.2 Hz, 1H), 7.32 (br d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 5.98 (br s, 1H), 4.07-4.26 (m, 2H), 3.85-4.06 (m, 2H), 3.78 (br s, 1H), 3.37 (s, 2H), 2.93-3.12 (m, 2H), 2.59-2.76 (m, 1H), 2.39-2.58 (m, 1H), 2.15 (br dd, J = 13.0, 6.7 Hz, 1H), 1.12 (br d, J = 6.4 Hz, 6H); 1H not observed (NH or OH) 298 MS m/z 410.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.93 (s, 1H), 7.89 (br s, 2H), 7.70 (d, J = 7.9 Hz, 1H), 7.11 (dd, J = 8.2, 1.8 Hz, 1H), 7.08 (d, J = 1.5 Hz, 1H), 4.64-4.73 (m, 1H), 3.39 (br d, J = 7.9 Hz, 1H), 2.15 (br dd, J = 13.3, 8.4 Hz, 1H), 1.78 (dd, J = 13.3, 6.3 Hz, 1H), 1.33 (s, 3H), 1.31 (s, 3H), 1.22 (s, 3H), 1.18 (s, 3H); 5Hs not observed (3 NHs and 2 OHs) 306 MS m/z 364.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 10.05 (br s, 1H), 9.13 (s, 1H), 8.91 (br s, 1H), 8.10 (s, 2H), 7.86 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 7.32 (s, 1H), 7.17-7.26 (m, 3H), 3.76-4.01 (m, 4H), 3.51-3.69 (m, 1H), 2.85-2.97 (m, 1H), 2.73-2.85 (m, 1H), 1.64-1.88 (m, 5H) 309 MS m/z 339.3 [M + H]⁺ 310 MS m/z 378.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 10.40 (br s, 1H), 9.10-9.19 (m, 1H), 8.12 (s, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.19-7.29 (m, 2H), 4.15- 4.32 (m, 2H), 3.62-3.70 (m, 2H), 3.30-3.40 (m, 1H), 3.17 (s, 3H), 2.97-3.08 (m, 1H), 2.87-2.95 (m, 1H), 1.72-1.95 (m, 5H); 1H not observed (OH or NH) 311 MS m/z 380.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 12.38 (br s, 1H), 9.13 (s, 1H), 8.11 (s, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.18-7.30 (m, 2H), 5.76 (s, 1H), 4.50 (s, 3H), 4.14-4.22 (m, 2H), 3.99-4.03 (m, 2H), 3.86-3.95 (m, 2H), 3.80-3.84 (m, 2H), 3.36-3.49 (m, 1H), 3.26-3.29 (m, 1H) 312 MS m/z 380.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.08 (s, 1H), 8.27-7.95 (m, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.28-7.17 (m, 2H), 4.67 (q, J = 6.3 Hz, 2H), 4.52-4.31 (m, 2H), 4.07-3.86 (m, 2H), 3.76-3.53 (m, 4H), 2.14-2.02 (m, 1H), 1.82 (br s, 1H); 3Hs not observed (2NHs and OH) 313 MS m/z 394.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.10 (s, 1H), 8.16 (s, 1H), 7.90-7.82 (m, 2H), 7.20- 7.14 (m, 2H), 4.80-4.871 (m, 2H), 4.58-4.55 (m, 2H), 4.45-4.34 (m, 1H), 3.88 (s, 3H), 3.85-3.72 (m, 3H), 3.70-3.59 (m, 2H), 2.35-2.22 (m, 1H), 2.15-2.03 (m, 1H); 2Hs not observed (NH and OH) 316 MS m/z 398.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.10 (s, 1H), 8.00 (br s, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.19 (s, 1H), 4.52 (d, J = 47.5 Hz, 2H), 4.18-4.13 (m, 2H), 3.96-3.93 (m, 1H), 3.72-3.64 (m, 2H), 2.58-2.55 (m, 1H), 2.24-2.16 (m, 1H), 1.41 (s, 6H); 3Hs not observed (2 NHs and OH) 317 MS m/z 352.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.50 (s, 2H), 7.69 (br d, J = 7.9 Hz, 1H), 7.33 (br d, J = 8.5 Hz, 1H), 7.31 (s, 1H), 5.99 (s, 1H), 4.04-4.29 (m, 2H), 3.94 (br d, J = 12.2 Hz, 2H), 3.73-3.86 (m, 1H), 3.24 (dt, J = 12.6, 6.1 Hz, 2H), 2.57-2.75 (m, 1H), 2.33-2.56 (m, 1H), 1.43 (br t, J = 6.9 Hz, 3H) 3Hs not observed (2 NHs 1 OH) 318 MS m/z 352.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.59 (br s, 2H), 7.70 (br d, J = 7.9 Hz, 1H), 7.34 (br d, J = 8.2 Hz, 1H), 7.32 (br s, 1H), 5.91-6.08 (m, 1H), 4.14-4.33 (m, 2H), 4.05-3.90 (m, 2H), 3.72-3.83 (m, 1H), 3.04 (s, 3H), 3.04 (s, 3H), 2.71 (br d, J = 6.1 Hz, 1H), 2.41-2.62 (m, 1H); 2Hs not observed (NH and OH) 322 MS m/z 412.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.02 (s, 1H), 8.00 (br s, 2H), 7.78 (br d, J = 7.9 Hz, 1H), 7.20 (br d, J = 8.2 Hz, 1H), 7.18 (s, 1H), 4.65-4.80 (m, 1H), 4.45-4.60 (m, 1H), 1.78 (br d, J = 8.5 Hz, 2H), 1.38 (br d, J = 6.7 Hz, 6H), 1.27 (s, 6H); 4Hs not observed (3NHs and OH) 323 MS m/z 412.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.05 (s, 1H), 8.01 (br s, 2H), 7.81 (br d, J = 7.9 Hz, 1H), 7.22 (br d, J = 8.2 Hz, 1H), 7.20 (s, 1H), 4.66-4.80 (m, 1H), 4.43-4.61 (m, 1H), 1.78 (br d, J = 8.5 Hz, 2H), 1.38 (br d, J = 7.0 Hz, 6H), 1.27 (s, 6H); 4Hs not observed (3NHs and OH) 325 MS m/z 394.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.13 (s, 1H), 8.08 (br s, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.31-7.16 (m, 2H), 4.84-4.70 (m, 2H), 4.48 (d, J = 6.9 Hz, 2H), 4.18-4.04 (m, 1H), 4.04-3.90 (m, 1H), 3.90-3.79 (m, 1H), 3.79- 3.69 (m, 1H), 3.69-3.56 (m, 1H), 2.46-2.36 (m, 1H), 2.23-2.09 (m, 1H), 1.73 (s, 3H); 3Hs not observed (2 NH and OH) 327 MS m/z 364.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.08-9.24 (m, 2H), 8.94 (br s, 1H), 8.12 (s, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.19-7.28 (m, 2H), 3.56-3.80 (m, 4H), 3.20-3.29 (m, 1H), 3.00-3.13 (m, 3H), 2.67-2.78 (m, 1H), 2.57-2.67 (m, 1H), 1.91-2.04 (m, 1H), 1.68-1.81 (m, 1H); 1H not observed (OH or NH) 328 MS m/z 324.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.13 (s, 1H), 8.24 (s, 2H), 7.87 (br d, J = 7.8 Hz, 2H), 7.34-7.19 (m, 2H), 4.11 (br s, 4H), 3.22 (br s, 4H); 3Hs not observed (2 NHs and OH) 329 MS m/z 384.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.17 (s, 1H), 8.20 (br s, 2H), 7.84 (d, J = 7.3 Hz, 1H), 7.26 (br s, 2H), 4.97-4.57 (m, 3H), 4.22- 3.81 (m, 5H), 3.80-3.54 (m, 2H), 1.37 (br s, 3H); 3Hs was not observed (2 NHs and OH) 332 MS m/z 350.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.48 (s, 2H), 7.70 (br d, J = 8.5 Hz, 1H), 7.33 (br d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 6.00 (s, 1H), 3.93-4.05 (m, 1H), 3.82-3.92 (m, 1H), 3.48-3.62 (m, 2H), 3.39-3.48 (m, 1H), 2.46-2.68 (m, 3H), 2.27-2.45 (m, 2H); 3Hs not observed (2 NHs and OH) 333 MS m/z 368.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.47 (s, 2H), 7.68 (br d, J = 8.7 Hz, 1H), 7.33 (br d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 5.99 (s, 1H), 4.20- 4.33 (m, 1H), 4.19-4.09 (m, 2H), 3.91 (br s, 5H), 3.75- 3.85 (m, 1H), 3.37 (s, 1H), 2.60-2.76 (m, 1H), 2.38- 2.57 (m, 1H); 3Hs not observed (2 NHs and OH) 334 MS m/z 366.3 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 13.00 (br s, 1H), 11.43 (br s, 1H), 9.09 (s, 1H), 8.23 (br s, 1H), 7.95 (br s, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.20- 7.24 (m, 2H), 4.80-4.88 (m, 1H), 4.40-4.52 (m, 3H), 3.82- 4.01 (m, 2H), 3.49-3.73 (m, 3H); 2Hs not observed (OH and/or NH) 335 MS m/z 408.4 [M + H]⁺ 336 MS m/z 396.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.63 (br s, 2H), 7.70 (br s, 1H), 7.33 (br s, 2H), 5.99 (br s, 1H), 4.36 (br s, 1H), 4.15 (br s, 1H), 4.05-3.87 (m, 2H), 3.79 (m, 2H), 3.63-3.56 (m, 2H), 3.48 (br s, 3H), 2.78-2.33 (m, 2H), 1.47 (br s, 3H); 3Hs was observed (2NHs and OH) 337 MS m/z 350.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.81 (s, 2H), 7.72 (d, J = 7.93 Hz, 1H), 7.40-7.35 (m, 2H), 5.98 (s, 1H), 3.98 (br s, 2H), 3.79-3.77 (m, 2H), 3.71-3.61 (m, 2H), 3.49-3.40 (m, 4H); 3Hs not observed (2 NHs and OH) 339 MS m/z 364.2 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.79 (br s, 1H), 9.68 (br s, 1H), 9.13 (s, 1H), 8.10 (s, 2H), 7.86 (d, J = 8.5 Hz, 1H), 7.19-7.27 (m, 2H), 4.11-4.24 (m, 1H), 3.78-3.85 (m, 1H), 3.66-3.69 (m, 1H), 3.28-3.33 (m, 2H), 2.55- 2.61 (m, 1H), 2.25-2.39 (m, 2H), 1.96-2.17 (m, 4H); 1H not observed (OH or NH) 340 MS m/z 378.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.65 (s, 2H), 7.68 (d, J = 8.1 Hz, 1H), 7.42-7.24 (m, 2H), 6.04-5.91 (m, 1H), 4.50-4.36 (m, 1H), 4.22-4.11 (m, 1H), 4.04-3.88 (m, 2H), 3.84-3.71 (m, 1H), 2.73-2.60 (m, 1H), 2.60-2.42 (m, 1H), 1.58 (d, J = 2.9 Hz, 3H), 1.31 (br s, 2H), 0.90 (br d, J = 4.0 Hz, 2H); 3Hs not observed (2 NHs and OH) 341 MS m/z 410.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.69 (s, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.42-7.30 (m, 2H), 5.99 (s, 1H), 4.45-4.27 (m, 1H), 4.21-4.03 (m, 1H), 4.02-3.87 (m, 2H), 3.85-3.73 (m, 1H), 3.62-3.47 (m, 5H), 2.73-2.59 (m, 1H), 2.56-2.40 (m, 1H), 1.57-1.43 (m, 6H); 3Hs not observed (2 NHs and OH) 345 MS m/z 356.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.60 (br s, 2H), 7.80-7.51 (m, 1H), 7.45-7.16 (m, 2H), 6.12-5.81 (m, 1H), 5.38-5.12 (m, 1H), 4.52-4.22 (m, 1H), 3.93-3.71 (m, 1H), 3.67-3.41 (m, 3H), 2.45-2.10 (m, 2H); 4Hs not observed (3 NHs and OH) 346 MS m/z 368.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.55 (s, 2H), 7.63-7.55 (m, 1H), 7.30-7.15 (m, 2H), 5.89 (s, 1H), 4.38 (br s, 1H), 4.11-3.90 (m, 4H), 3.70-3.59 (m, 1H), 3.42 (d, J = 2.4 Hz, 3H), 2.78 (d, J = 3.8 Hz, 3H); 3Hs not observed (2 NHs and OH) 347 MS m/z 366.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.05 (s, 1H), 7.99 (br s, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0, 2.0 Hz, 1H), 7.17 (d, J = 1.5 Hz, 1H), 3.99 (dd, J = 11.5, 6.5 Hz, 1H), 3.89-3.85 (m, 1H), 3.79-3.73 (m, 1H), 3.68-3.62 (m, 1H), 3.47 (dd, J = 11.5, 6.5 Hz, 1H), 3.10 (dt, J = 12.5, 6.0 Hz, 1H), 2.39 (dq, J = 12.0, 6.0 Hz, 1H), 2.03-1.97 (m, 1H), 1.20 (t, J = 5.5 Hz, 6H); 3Hs not observed (2 NHs and OH) 348 MS m/z 366.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.05 (s, 1H), 7.99 (br s, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.0, 2.0 Hz, 1H), 7.17 (d, J = 1.5 Hz, 1H), 3.99 (dd, J = 11.5, 6.5 Hz, 1H), 3.89-3.85 (m, 1H), 3.79-3.73 (m, 1H), 3.68-3.62 (m, 1H), 3.47 (dd, J = 11.5, 6.5 Hz, 1H), 3.10 (dt, J = 12.5, 6.0 Hz, 1H), 2.39 (dq, J = 12.0, 6.0 Hz, 1H), 2.03-1.97 (m, 1H), 1.20 (t, J = 5.5 Hz, 6H); 3Hs not observed (2 NHs and OH) 349 MS m/z 390.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.20-11.34 (m, 1H), 9.50-9.59 (m, 1H), 9.13 (s, 1H), 8.07-8.12 (m, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 4.03-4.08 (m, 1H), 3.95-4.00 (m, 1H), 3.78-3.84 (m, 2H), 3.66-3.75 (m, 3H), 2.74 (s, 1H), 2.11-2.15 (m, 6H); 2Hs not observed (2 NHs) 353 MS m/z 380.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.64 (s, 2H), 7.70 (d, J = 8.1 Hz, 1H), 7.40-7.29 (m, 2H), 5.97 (d, J = 10.1 Hz, 1H), 4.12-4.04 (m, 2H), 4.02-3.95 (m, 1H), 3.94-3.70 (m, 3H), 3.59-3.44 (m, 2H), 2.68-2.53 (m, 1H), 2.37-2.20 (m, 1H); 2Hs not observed (overlapped with residual solvent peak); 3Hs not observed (2 NHs and OH) 354 MS m/z 364.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.59 (br s, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.40- 7.26 (m, 2H), 6.01-5.94 (m, 1H), 3.88-3.67 (m, 4H), 3.59-3.43 (m, 4H), 2.41-2.10 (m, 4H); 3Hs not observed (2 NHs and OH) 355 MS m/z 380.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.25 (br s, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.5, 1.5 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 4.38-4.28 (m, 1H), 4.18- 4.12 (m, 1H), 3.96-3.87 (m, 2H), 3.80-3.70 (m, 1H), 2.72- 2.64 (m, 1H), 2.49-2.37 (m, 1H), 1.51 (s, 9H); 3Hs not observed (2NHs and OH) 356 MS m/z 380.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.25-8.16 (m, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.25 (s, 1H), 5.98 (d, J = 2.6 Hz, 1H), 4.40-4.29 (m, 1H), 4.20-4.13 (m, 1H), 3.96- 3.87 (m, 2H), 3.80-3.71 (m, 1H), 2.76-2.64 (m, 1H), 2.49- 2.37 (m, 1H), 1.53 (s, 9H); 3Hs not observed (2 NHs and OH) 357 MS m/z 392.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.12 (s, 1H), 7.90-8.17 (m, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.21 (s, 2H), 4.09-4.16 (m, 1H), 4.02-4.09 (m, 1H), 3.89-4.00 (m, 1H), 3.74-3.83 (m, 2H), 3.59-3.70 (m, 1H), 2.46-2.65 (m, 1H), 2.13-2.32 (m, 3H), 1.80-1.92 (m, 2H), 1.58-1.78 (m, 4H); 3Hs not observed (2NHs and OH) 361 MS m/z 380.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.62 (br s, 2H), 7.68 (d, J = 7.9 Hz, 1H), 7.42-7.28 (m, 2H), 5.95 (d, J = 7.2 Hz, 1H), 4.02-3.89 (m, 1H), 3.88-3.78 (m, 1H), 3.77-3.64 (m, 1H), 3.51-3.44 (m, 1H), 3.30-3.17 (m, 2H), 2.89 (br s, 1H), 2.44 (br s, 1H), 2.14-1.94 (m, 1H), 1.50-1.38 (m, 7H); 3Hs not observed (2NHs and OH) 362 MS m/z 422.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.13 (s, 1H), 8.05 (d, J = 9.6 Hz, 2H), 7.30-7.16 (m, 2H), 5.96 (s, 1H), 4.47-4.29 (m, 1H), 4.27-4.09 (m, 1H), 4.04-3.98 (m, 2H), 3.83-3.69 (m, 2H), 3.65 (br t, J = 11.6 Hz, 3H), 2.75-2.58 (m, 1H), 2.51- 2.25 (m, 1H), 2.07-1.95 (m, 2H), 1.94-1.82 (m, 2H), 1.64 (br s, 3H); 3Hs not observed (2 NHs and OH) 367 MS m/z 397.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.11 (s, 1H), 7.95 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.19 (s, 1H), 5.97 (d, J = 2.1 Hz, 1H), 4.28-4.42 (m, 1H), 4.09-4.22 (m, 1H), 3.84-3.99 (m, 2H), 3.69-3.82 (m, 1H), 2.62- 2.77 (m, 1H), 2.36-2.51 (m, 1H), 1.52 (s, 9H); 2Hs not observed (NH and OH) 373 MS m/z 411.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.14 (s, 1H), 7.99 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 8.2, 1.5 Hz, 1H), 7.19 (d, J = 1.5 Hz, 1H), 5.92-6.03 (m, 1H), 4.23-4.43 (m, 1H), 2.20-2.33 (m, 2H), 1.68-1.87 (m, 2H), 1.63 (d, J = 8.9 Hz, 6H), 1.55 (d, J = 6.4 Hz, 6H); 3Hs not observed (2 NHs and OH) 369 MS m/z 378.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.63 (s, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.41-7.27 (m, 2H), 5.96 (d, J = 6.4 Hz, 1H), 3.80 (br s, 3H), 3.32-3.19 (m, 4H), 2.36-2.08 (m, 2H), 2.02- 1.76 (m, 5H); 3Hs not observed (2 NHs and OH) 370 MS m/z 350.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.54 (s, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.37- 7.26 (m, 2H), 5.99 (d, J = 9.0 Hz, 1H), 4.63- 4.50 (m, 1H), 4.26-4.16 (m, 1H), 4.10 (dd, J = 6.3, 12.4 Hz, 1H), 4.06-.98 (m, 1H), 3.67-3.54 (m, 2H), 3.54-3.43 (m, 2H), 2.48-2.36 (m, 1H), 2.22-2.12 (m, 1H); 3Hs not observed (2 NHs and OH) 371 MS m/z 382.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.15 (s, 1H), 8.15 (br s, 2H), 7.85 (d, J = 8.2 Hz, 1H), 7.29-7.20 (m, 2H), 3.98 (br s, 2H), 3.94- 3.84 (m, 2H), 3.72-3.61 (m, 1H), 3.52 (br t, J = 5.7 Hz, 2H), 3.11-2.98 (m, 2H), 2.45- 2.35 (m, 2H), 1.92-1.80 (m, 2H); 4Hs not observed (2 NHs and 2 OHs) 372 MS m/z 422.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.95 (s, 1H), 7.99 (br s, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.18-7.08 (m, 2H), 4.09-4.02 (m, 2H), 3.94-3.86 (m, 1H), 3.82-3.74 (m, 1H), 3.58-3.44 (m, 3H), 3.30- 3.23 (m, 1H), 3.21-3.14 (m, 2H), 2.75-2.64 (m, 1H), 2.37-2.25 (m, 1H), 2.11-2.01 (m, 2H), 1.91-1.79 (m, 1H), 1.76-1.64 (m, 2H); 1H not observed (overlapped with solvent peak); 3Hs not observed (2 NHs and OH) 377 MS m/z 429.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.15 (s, 1H), 8.00 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 8.2, 1.2 Hz, 1H), 7.20 (s, 1H), 6.01 (d, J = 10.1 Hz, 1H), 4.62-4.82 (m, 1H), 1.97-2.27 (m, 3H), 1.65-1.72 (m, 6H), 1.55-1.63 (m, 6H); 3Hs not observed (2 NHs and OH) 386 MS m/z 406.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.66 (s, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.42-7.29 (m, 2H), 6.02-5.89 (m, 1H), 4.04-3.88 (m, 1H), 3.87- 3.76 (m, 1H), 3.74-3.59 (m, 2H), 3.51-3.42 (m, 1H), 3.31-3.20 (m, 2H), 3.00-2.81 (m, 1H), 2.53-2.37 (m, 1H), 2.25-2.14 (m, 2H), 2.12-1.97 (m, 1H), 1.89 (br s, 2H), 1.83-1.75 (m, 2H), 1.71 (br s, 2H); 3Hs not observed (2 NHs and OH) 387 MS m/z 378.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.17 (s, 1H), 8.19-8.09 (m, 2H), 7.80 (br d, J = 5.6 Hz, 1H), 7.25 (br s, 2H), 3.93-3.74 (m, 1H), 3.65- 3.51 (m, 1H), 3.51-3.32 (m, 2H), 3.28-3.08 (m, 2H), 2.38-2.27 (m, 1H), 2.25-2.09 (m, 2H), 2.05-1.93 (m, 2H), 1.93-1.78 (m, 2H), 1.73-1.56 (m, 1H); 3Hs not observed (2 NHs and OH) 388 MS m/z 429.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.10 (s, 1H), 8.68 (s, 1H), 8.09 (s, 2H), 7.99-7.79 (m, 2H), 7.62-7.39 (m, 2H), 7.31-7.14 (m, 2H), 4.40 (br s, 2H), 3.98-3.87 (m, 1H), 3.80-3.75 (m, 1H), 3.66-3.52 (m, 1H), 3.51-3.38 (m, 1H), 3.19 (br s, 2H), 2.87- 2.72 (m, 1H), 2.31-2.20 (m, 1H), 1.95-1.81 (m, 1H); 3Hs not observed (2 NHs and OH) 389 MS m/z 352.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.08 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.00 Hz, 1H), 7.19 (d, J = 8.00 Hz, 1H), 7.16 (s, 1H), 3.96 (s, 3H), 3.92-3.81 (m, 2H), 3.75 (d, J = 11.00 Hz, 1H), 3.62 (d, J = 11.00 Hz, 1H), 2.16 (s, 2H), 1.49 (s, 3H); 3Hs not observed (2 NHs and OH) 390 MS m/z 394.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.68 (s, 2H), 7.69 (d, J = 7.9 Hz, 1H), 7.40-7.29 (m, 2H), 5.96 (d, J = 7.8 Hz, 1H), 4.06-3.91 (m, 1H), 3.90-3.78 (m, 1H), 3.77-3.64 (m, 1H), 3.61-3.44 (m, 1H), 3.31-3.17 (m, 2H), 2.96-2.80 (m, 1H), 2.54- 2.41 (m, 1H), 2.16-1.97 (m, 1H), 1.53-1.43 (s, 9H); 3Hs not observed (2 NHs and OH) 391 MS m/z 436.6 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.11 (s, 1H), 8.50-8.64 (m, 1H), 8.46 (br dd, J = 3.7, 1.8 Hz, 1H), 8.03-8.23 (m, 2H), 7.86 (br d, J = 8.4 Hz, 2H), 7.19-7.28 (m, 2H), 3.88-4.02 (m, 2H), 3.85 (br dd, J = 10.5, 2.0 Hz, 2H), 3.71-3.82 (m, 2H), 3.56- 3.70 (m, 2H), 3.42-3.52 (m, 3H), 3.04-3.25 (m, 3H), 2.60- 2.75 (m, 1H), 2.16-2.37 (m, 2H), 1.77-1.94 (m, 3H), 1.57-1.77 (m, 3H), 1.42 (s, 3H) 392 MS m/z 378.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 11.48 (br s, 1H), 9.09 (s, 1H), 8.15 (s, 1H), 7.99-8.12 (m, 1H), 7.85 (br d, J = 8.2 Hz, 1H), 7.17-7.26 (m, 2H), 3.77-3.91 (m, 1H), 3.66-3.77 (m, 1H), 3.50- 3.62 (m, 1H), 2.77-2.93 (m, 2H), 2.26-2.35 (m, 1H), 2.08-2.25 (m, 1H), 1.80 (br d, J = 9.6 Hz, 1H), 0.51 (br d, J = 5.6 Hz, 2H), 0.44 (br s, 2H); 4H not observed (2NHs, 2 aliphatic CHs obscured by solvent peak) 395 MS m/z 408.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.41 (s, 2H), 7.66 (d, J = 8.2 Hz, 1H), 7.24- 7.36 (m, 2H), 5.95 (d, J = 6.7 Hz, 1H), 4.05- 4.15 (m, 2H), 3.90-4.01 (m, 2H), 3.87-3.89 (m, 1H), 3.74-3.86 (m, 2H), 3.65-3.71 (m, 1H), 3.41-3.52 (m, 2H), 2.82-2.92 (m, 1H), 2.40-2.50 (m, 2H), 2.16 (br s, 1H), 2.00-2.17 (m, 2H); 3Hs not observed (OH and 2NHs) 397 MS m/z 422.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.07 (s, 1H), 8.01 (br d, J = 0.9 Hz, 2H), 7.83 (br d, J = 7.3 Hz, 1H), 7.23 (br d, J = 8.2 Hz, 1H), 7.20 (s, 1H), 3.92-4.05 (m, 3H), 3.82-3.90 (m, 1H), 3.59-3.69 (m, 1H), 3.45 (br t, J = 11.7 Hz, 2H), 2.83 (br d, J = 7.0 Hz, 3H), 2.53-2.64 (m, 1H), 2.26-2.35 (m, 1H), 1.93 (br d, J = 12.8 Hz, 2H), 1.80-1.88 (m, 1H), 1.42-1.54 (m, 2H), 1.28- 1.38 (m, 1H); 3Hs not observed (2NHs and OH) 398 MS m/z 422.4 [M + H]⁺; ¹H NMR (1:3 chloroform-d: methanol-d₄) δ: 9.04 (s, 1H), 7.94 (br s, 2H), 7.78 (br d, J = 7.9 Hz, 1H), 7.15-7.23 (m, 2H), 4.03 (br d, J = 11.0 Hz, 2H), 3.98 (br dd, J = 9.8, 8.9 Hz, 1H), 3.84-3.92 (m, 1H), 3.62-3.71 (m, 1H), 3.46 (br t, J = 11.6 Hz, 2H), 3.35-3.40 (m, 1H), 2.89- 3.14 (m, 3H), 2.59-2.72 (m, 1H), 2.28-2.38 (m, 1H), 1.98 (br d, J = 11.9 Hz, 2H), 1.82-1.93 (m, 1H), 1.51-1.64 (m, 2H); 3Hs not observed (2 NHs and OH) 399 MS m/z 378.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 1.94-2.09 (m, 2H) 2.28-2.52 (m, 4H) 2.54-2.69 (m, 1H) 3.37 (s, 1H), 3.71-4.02 (m, 4H) 4.03-4.18 (m, 2H) 5.98 (br s, 1H) 7.20-7.42 (m, 2H) 7.67 (br d, J = 8.24 Hz, 1H) 8.41 (br s, 2H); 3Hs not observed (2NHs and OH) 400 MS m/z 378.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 1.91-2.09 (m, 2H) 2.28-2.50 (m, 5H) 2.52-2.71 (m, 1H) 3.37 (s, 2H) 3.68-4.01 (m, 4H) 4.03-4.19 (m, 2H) 5.93-6.03 (m, 1H) 7.31 (s, 1H) 7.32-7.37 (m, 1H) 7.69 (br d, J = 7.93 Hz, 1H) 8.55 (s, 2H); 1H not observed 403 MS m/z 440.7 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.41 (s, 2H), 7.67 (d, J = 7.9 Hz, 1H), 7.25-7.34 (m, 2H), 5.95 (d, J = 7.3 Hz, 1H), 5.11-5.13 (m, 1H), 5.02-5.04 (m, 1H), 4.22 (t, J = 13.4 Hz, 1H), 4.09 (d, J = 10.4 Hz, 1H), 3.95-4.01 (m, 1H), 3.70-3.85 (m, 4H), 3.47-3.64 (m, 3H), 2.90-2.94 (m, 1H), 2.46-2.50 (m, 1H), 1.97-2.20 (m, 3H); 3Hs not observed (OH and 2NHs) 404 MS m/z 422.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.40 (s, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.25-7.35 (m, 2H), 5.95 (d, J = 6.4 Hz, 1H), 3.90-4.05 (m, 2H), 3.74-3.87 (m, 3H), 3.68-3.72 (m, 2H), 3.47-3.52 (m, 2H), 3.35-3.37 (m, 2H), 2.88-2.94 (m, 1H), 2.44- 2.48 (m, 1H), 2.19-2.22 (m, 1H), 1.92-2.10 (m, 3H), 1.68-1.72 (m, 1H); 3Hs not observed (OH and 2NHs) 405 MS m/z 448.7 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.42 (br s, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.26- 7.36 (m, 2H), 5.95 (d, J = 6.7 Hz, 1H), 4.50- 4.52 (m, 2H), 3.92-3.96 (m, 1H), 3.79-3.83 (m, 1H), 3.66-3.72 (m, 1H), 3.47-3.52 (m, 2H), 3.15-3.28 (m, 2H), 2.85-2.89 (m, 1H), 2.65-2.72 (m, 2H), 2.40-2.46 (m, 1H), 2.00-2.10 (m, 2H), 1.82 (d, J = 7.3 Hz, 2H), 1.45-1.62 (m, 2H), 1.26-1.31 (m, 1H); 3Hs not observed (OH and 2NHs) 406 MS m/z 392.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 1.97-2.07 (m, 2H) 2.29-2.52 (m, 5H) 2.53-2.69 (m, 1H) 3.71-4.02 (m, 4H) 4.08 (br s, 5H) 5.97 (br s, 1H) 7.24 (br s, 1H) 7.26 (br d, J = 8.24 Hz, 1H) 7.66 (br d, J = 8.24 Hz, 1H) 8.17-8.53 (m, 2H); 3Hs not observed (2NHs and OH) 407 MS m/z 392.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 1.89-2.08 (m, 2H) 2.23-2.51 (m, 5H) 2.60 (br d, J = 5.80 Hz, 1H) 3.69-4.00 (m, 4H) 4.01-4.20 (m, 5H) 5.97 (br s, 1H) 7.22 (s, 1H) 7.25 (br d, J = 7.93 Hz, 1H) 7.65 (br d, J = 7.93 Hz, 1H) 8.17 (s, 1H) 8.29 (s, 1H); 3Hs not observed (2 NHs and OH) 408 MS m/z 420.6 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.10 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.83 (d, J = 8.54 Hz, 1H), 7.21 (d, J = 8.09 Hz, 1H), 7.17 (s, 1H), 3.38-3.28 (m, 1H), 3.96 (s, 3H), 3.20 (s, 3H), 2.36-2.30 (m, 2H), 2.14-1.99 (m, 6H), 1.57 (s, 6H); 2Hs not observed (NH and OH) 409 MS m/z 428.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.47 (br s, 2H), 7.69 (br d, J = 8.2 Hz, 1H), 7.33 (br d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 5.99 (s, 1H), 4.20-4.30 (m, 1H), 4.07-4.19 (m, 1H), 3.86-4.07 (m, 3H), 3.75-3.86 (m, 1H), 2.75-2.88 (m, 1H), 2.60-2.74 (m, 1H), 2.32-2.56 (m, 4H), 2.15-2.30 (m, 1H), 2.02- 2.12 (m, 1H); 3Hs not observed (2NHs and OH) 410 MS m/z 366.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.42 (s, 2H), 7.66 (d, J = 7.8 Hz, 1H), 7.35- 7.25 (m, 2H), 5.95 (d, J = 9.0 Hz, 1H), 4.07- 3.92 (m, 1H), 3.89-3.76 (m, 1H), 3.74-3.61 (m, 1H), 3.56-3.46 (m, 1H), 3.45-3.38 (m, 2H), 3.00 (br s, 7H), 2.51-2.39 (m, 1H), 2.12-1.92 (m, 1H); 2Hs not observed (NH and OH) 413 MS m/z 352.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.46 (s, 2H), 7.71-7.62 (m, 1H), 7.36-7.26 (m, 2H), 5.99-5.89 (m, 1H), 4.00-3.88 (m, 1H), 3.81 (br s, 1H), 3.74-3.63 (m, 1H), 3.56-3.47 (m, 1H), 3.28-3.25 (m, 2H), 2.95-2.84 (m, 1H), 2.84-2.77 (m, 3H), 2.43 (m, 1H), 2.13-1.93 (m, 1H); 3Hs not observed (2NHs and OH) 414 MS m/z 394.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.51 (s, 2H), 7.67 (d, J = 7.8 Hz, 1H), 7.40-7.25 (m, 2H), 6.01-5.87 (m, 1H), 3.99-3.79 (m, 1H), 3.74- 3.57 (m, 3H), 2.94-2.79 (m, 1H), 2.59-2.27 (m, 1H), 2.16-1.99 (m, 1H), 1.52-1.35 (m, 11H); 3Hs not observed (2NHs and OH) 415 MS m/z 392.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 1.89-2.08 (m, 2H) 2.23-2.51 (m, 5H) 2.60 (br d, J = 5.80 Hz, 1H) 3.69-4.00 (m, 4H) 4.01- 4.20 (m, 5H) 5.97 (br s, 1H) 7.22 (s, 1H) 7.25 (br d, J = 7.93 Hz, 1H) 7.65 (br d, J = 7.93 Hz, 1H) 8.17 (s, 1H) 8.29 (s, 1H); 3Hs not observed (2NHs and OH) 416 MS m/z 406.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 1.20 (t, J = 6.87 Hz, 2H) 1.89-2.13 (m, 2H) 2.25-2.51 (m, 5H) 2.86 (br dd, J = 12.51, 6.10 Hz, 1H) 3.04-3.22 (m, 2H), 3.51 (q, J = 6.82 Hz, 2H) 3.69 (br d, J = 6.10 Hz, 1H) 3.75-3.98 (m, 3H) 4.00-4.08 (m, 3 H) 5.94 (br d, J = 7.32 Hz, 1H) 7.22 (s, 1H) 7.25 (br d, J = 8.24 Hz, 1H) 7.63 (br d, J = 8.54 Hz, 1H) 8.16 (s, 1H) 8.28 (s, 1H) 418 MS m/z 398.5 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.13 (s, 1H), 8.14 (s, 2H), 7.69 (d, J = 7 Hz, 1H), 7.33 (t, J = 7 Hz, 1H), 4.16 (m, 1H), 4.07 (m, 1H), 3.75-3.90 (m, 2H), 3.64 (m, 1H), 2.35 (m, 1H), 1.38 (s, 9H); 3Hs not observed (NH, OH, and one aliphatic multiplet peak obscured by solvent peak) 420 MS m/z 410.4 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.81 (s, 2H), 7.69 (br d, J = 7.9 Hz, 1H), 7.30-7.42 (m, 2H), 5.98 (s, 1H), 5.27-5.35 (m, 1H), 4.28 (br s, 1H), 4.11-4.22 (m, 1H), 3.93-4.09 (m, 3H), 3.83 (br s, 1H), 2.69 (br d, J = 1.2 Hz, 1H), 2.48-2.64 (m, 2H), 2.43 (br s, 1H), 1.92-2.35 (m, 4H); 3Hs not observed (2 NHs and OH) 421 MS m/z 448.3 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 8.72 (br s, 2H), 7.70 (br d, J = 7.9 Hz, 1H), 7.32-7.39 (m, 2H), 5.90-6.04 (m, 1H), 4.06 (br d, J = 7.6 Hz, 4H), 3.77-3.88 (m, 1H), 3.65-3.75 (m, 1H), 3.48-3.63 (m, 3H), 3.16-3.27 (m, 1H), 2.34 (br d, J = 4.6 Hz, 1H), 2.21 (br d, J = 6.1 Hz, 1H), 2.14 (br d, J = 11.9 Hz, 1H), 1.79 (br s, 3H), 1.14 (br d, J = 6.1 Hz, 4H); 3Hs not observed (2 NHs and OH) 422 MS m/z 394.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.14 (s, 1H), 8.02 (s, 1H), 7.86 (s, 1H), 7.84 (d, J = 10.00 Hz, 1H), 7.21 (d, J = 10.00 Hz, 1H), 7.18 (s, 1H), 4.06-3.89 (m, 3H), 3.96 (s, 3H), 3.86-3.74 (m, 2H), 2.44-2.37 (m, 2H), 1.65 (s, 3H), 1.46 (t, J = 5.50 Hz, 6H); 2Hs not observed (NH and OH)

Example 7 Preparation of Compound 14

Step 1.

To a dry round bottom flask were added: 6-bromo-3-methylsulfanyl-1,2,4-triazine (7.0 g, 34.0 mmol), 2-[4-chloro-2-(methoxymethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10 g, 33.5 mmol), K₂CO₃ (9.5 g, 68 mmol), and PddppfCl2 (3.8 g, 5.1 mmol). The mixture was degassed with argon for 10 min, then dioxane (100 mL) and water (20 mL) were added and the reaction was heated at 90° C. for 16 h (overnight). The reaction was cooled down to room temperature, partitioned between EtOAc and water, and then the organic phase was dried over Na₂SO₄, concentrated, and then purified by silica-gel column chromatography eluting with a gradient of 0-20% EtOAc in pentanes. This provided 6-[4-chloro-2-(methoxymethoxy)phenyl]-3-methylsulfanyl-1,2,4-triazine (4.5 g, 44% yield) as a yellow solid. MS m/z 298.1, 300.1 [M+H]⁺.

Step 2.

6-[4-Chloro-2-(methoxymethoxy)phenyl]-3-methylsulfanyl-1,2,4-triazine (1.84 g, 6.18 mmol) and mCPBA (2.67 g, 15.5 mmol) were dissolved in CH₂Cl₂ (26 mL). The reaction mixture was stirred at room temperature for 16 h. LCMS showed full conversion. The solvent was then removed in vacuo and the crude product was triturated in 20 mL Et₂O. Filtration provided 6-[4-chloro-2-(methoxymethoxy)phenyl]-3-methylsulfonyl-1,2,4-triazine (1.69 g, 80.4% yield) as an off-white solid. MS m/z 330.1, 332.1 [M+H]⁺.

Step 3.

6-[4-Chloro-2-(methoxymethoxy)phenyl]-3-methylsulfonyl-1,2,4-triazine (1.0 g, 2.9 mmol) was dissolved in dry DMF (8 mL). Then N,2,2,6,6-pentamethylpiperidin-4-amine (790 mg, 4.41 mmol) and DIPEA (5.2 mL, 30 mmol) were added. The reaction mixture was stirred at 50° C. for 16 h (overnight). The reaction mixture was purified directly by silica-gel column chromatography using 20% MeOH/CH₂Cl₂ eluent to provide the desired product 6-[4-chloro-2-(methoxymethoxy)phenyl]-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (980 mg, 79% yield) as a yellow solid. MS m/z 420.5, 422.5 [M+H]⁺.

Step 4.

To a dry screw-cap vial were added 6-[4-chloro-2-(methoxymethoxy)phenyl]-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (30 mg, 0.071 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)pyrazole (18.1 mg, 0.086 mmol), XPhos Pd G4 (6 mg, 0.007 mmol), and K₂CO₃ (30 mg, 0.2143 mmol). The mixture was degassed with argon for 10 min, then dioxane (2 mL) and water (0.5 mL) were added and the reaction was heated at 90° C. for 16 h (overnight). The reaction was cooled to room temperature, partitioned between EtOAc and water, and the organic phase was dried over Na₂SO₄, concentrated, and purified by silica-gel column chromatography eluting with a MeOH/CH₂Cl₂ gradient (0-20% MeOH) to provide 6-[2-(methoxymethoxy)-4-[1-(trideuteriomethyl)pyrazol-4-yl]phenyl]-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (24 mg, 72% yield) as a brownish solid. MS m/z 469.8 [M+H]⁺.

Step 5.

To a solution 6-[2-(methoxymethoxy)-4-[1-(trideuteriomethyl)pyrazol-4-yl]phenyl]-N-methyl-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (24 mg, 0.051 mmol) in 1 mL of CH₂O₂ and a few drops of MeOH was added HCl (4 mol/L) in 1,4-dioxane (26H), 0.10 mmol) and the mixture was stirred 16 h at room temperature. UPLC showed complete consumption of the starting material. The solvents were evaporated and the residue was purified by silica-gel column chromatography eluting with a MeOH/CH₂Cl_(z) gradient (0-30% MeOH/2.5% NH₄OH) to provided 2-[3-[methyl-(2,2,6,6-tetramethyl-4-piperidyl) amino]-1,2,4-triazin-6-yl]-5-[1-(trideuteriomethyl)pyrazol-4-yl]phenol; hydrochloride (7 mg, 3000 yield) as a tan solid.

MS m/z 425.5 [M+H]; ¹H NMR (methanol-d₄) d: 9.58 (br s, 1H), 8.23 (s, 1H), 8.09 (s, 1H), 7.66 (d, J=18.2 Hz, 1H), 7.26 (dd, J=8.2, 1.8 Hz, 1H), 7.22 (d, J=1.8 Hz, 1H), 4.50-4.61 (m, 1H), 3.18 (s, 3H), 2.08-2.27 (m, 4H), 1.72 (s, 6H), 1.60 (s, 6H); 2Hs not observed (OH and NH).

Using the procedure described for Example 7, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data  72 MS m/z 413.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.34 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.27- 7.28 (m, 2H), 5.72-5.76 (m, 1H), 2.43-2.45 (m, 2H), 1.76-1.88 (m, 2H), 1.57 (s, 6H), 1.51 (s, 6H); 3Hs not observed (2NHs and OH) 213 MS m/z 380.3 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.14 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.64 (s, 1H), 7.32-7.52 (m, 2H), 6.67 (s, 1H), 4.06-4.25 (m, 2H), 3.98-4.03 (m, 1H), 3.97 (s, 3H), 3.71-3.91 (m, 1H), 3.43-3.61 (m, 1H), 2.58 (s, 1H), 2.21-2.33 (m, 1H), 2.28 (td, J = 13.0, 6.3 Hz, 1H), 1.42 (br t, J = 5.2 Hz, 6H); 2Hs not observed (NH and OH) 223 MS m/z 442.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.10 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.90 (d, J = 8.00 Hz, 1H). 7.7 (d, J = 8.50 Hz, 1H), 7.64 (d, J = 9.00 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.28 (s, 1H), 4.16 (s, 2H), 4.10 (s, 3H), 4.05 (s, 2H), 3.53 (d, J = 12.5 Hz, 2H), 3.11 (t, J = 12.5 Hz, 2H), 2.91 (s, 3H), 2.32 (d, J = 14.5 Hz, 2H), 2.05 (t, J = 12.50 Hz, 2H); 1H not observed (OH) 233 MS m/z 392.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 7.82 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.39 (s, 1H), 6.81 (s, 1H), 5.95 (s, 1H), 4.25 (s, 2H), 4.14 (s, 2H), 4.02 (s, 3H), 3.53 (d, J = 12.6 Hz, 2H), 3.14 (t, J = 12.7 Hz, 2H), 2.90 (s, 3H), 2.36 (d, J = 14.4 Hz, 2H), 2.13 (t, J = 13.8 Hz, 2H); 1 OH not observed 224 MS m/z 443.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.11 (s, 1H), 8.85 (s, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.00 Hz, 1H), 7.30 (s, 1H), 4.10-4.16 (m, 5H), 4.06 (s, 2H), 3.53 (d, J = 12.5 Hz, 2H), 3.12 (t, J = 10.00 Hz, 2H), 2.92 (s, 3H), 2.33 (d, J = 14.00 Hz, 2H), 2.05 (t, J = 14.50 Hz, 2H); 1H not observed (OH) 235 MS m/z 384.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.04 (s, 1H), 7.95 (s, 1H), 7.81 (d, J = 6.7 Hz, 1H), 7.09-7.27 (m, 2H), 3.96 (br dd, J = 9.8, 6.7 Hz, 1H), 3.76-3.91 (m, 1H), 3.51-3.71 (m, 2H), 3.35-3.42 (m, 1H), 2.98 (dt, J = 12.5, 6.3 Hz, 1H), 2.20-2.40 (m, 1H), 1.84-1.98 (m, 1H), 1.14 (t, J = 5.8 Hz, 6H); 3Hs not observed (2NHs and OH) 236 MS m/z 381.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.06 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.38-7.55 (m, 2H), 6.00 (d, J = 3.1 Hz, 1H), 4.26-4.37 (m, 1H), 4.24 (s, 3H), 4.08-4.19 (m, 1H), 3.74-4.02 (m, 3H), 3.51-3.65 (m, 1H), 2.58-2.74 (m, 1H), 2.34- 2.53 (m, 1H), 1.47 (d, J = 6.4 Hz, 6H); 2Hs not observed (NH and OH) 237 MS m/z 384.3 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.82 (s, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.59-7.73 (m, 2H), 6.03 (d, J = 3.1 Hz, 1H), 4.25-4.37 (m, 1H), 4.09-4.19 (m, 1H), 3.85-4.03 (m, 2H), 3.75-3.84 (m, 1H), 3.51-3.65 (m, 1H), 2.58-2.74 (m, 1H), 2.36-2.56 (m, 1H), 1.47 (br d, J = 5.8 Hz, 6H); 2Hs not observed (NH and OH) 260 MS m/z 476.5 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 9.51 (br d, J = 11.3 Hz, 1H), 9.10 (s, 1H), 8.21-8.31 (m, 1H), 8.15 (br d, J = 13.4 Hz, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H), 7.31-7.36 (m, 2H), 4.71-4.92 (m, 2H), 4.09 (s, 3H), 1.97-2.06 (m, 1H), 1.92 (br dd, J = 13.3, 4.1 Hz, 1H), 1.58 (s, 3H), 1.54 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H); 1H not observed (OH) 261 MS m/z 426.5 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 9.75 (br d, J = 11.3 Hz, 1H), 9.06 (s, 1H), 8.22 (br s, 1H), 8.13 (br d, J = 11.6 Hz, 1H),7.87 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.38 (dd, J = 8.2, 1.5 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 4.68-4.89 (m, 2H), 3.90 (s, 3H), 1.95-2.05 (m, 1H), 1.86-1.94 (m, 1H), 1.58 (s, 3H), 1.54 (s, 3H), 1.48 (br s, 3H), 1.47 (s, 3H) 263 MS m/z 366.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 7.89 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.50-7.41 (m, 2H), 6.88 (d, J = 2.4 Hz, 1H), 6.05 (s, 1H), 4.36 (d, J = 14.5 Hz, 1H), 4.23 (d, J = 13.7 Hz, 1H), 4.07 (s, 3H), 3.71-3.60 (m, 2H), 3.51- 3.38 (m, 2H), 1.50 (d, J = 6.4 Hz, 3H), 1.48 (d, J = 6.4 Hz, 3H); 2Hs was not observed (NH and OH) 289 MS m/z 381.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 7.95 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.39 (br d, J = 8.2 Hz, 1H), 7.35- 7.37 (m, 1H), 5.96-6.05 (m, 1H), 4.26-4.37 (m, 1H), 4.10-4.20 (m, 1H), 3.89-4.05 (m, 2H), 3.75-3.85 (m, 1H), 3.49-3.64 (m, 1H), 2.77 (s, 3H), 2.60-2.72 (m, 1H), 2.38-2.54 (m, 1H), 1.47 (dd, J = 6.4, 1.8 Hz, 6H); 2Hs not observed (NH and OH) 296 MS m/z 352.3 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 7.72 (d, J = 2 Hz, 1H), 7.68 (d, J = 8 Hz, 1H), 7.43 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.41 (s, 1H), 6.75 (d, J = 2 Hz, 1H), 5.99 (s, 1H), 4.03-4.18 (m, 2H), 4.00 (s, 3H), 3.87-3.95 (m, 2H), 3.81 (m, 1H), 2.85 (s, 3H), 2.59-2.74 (m, 1H), 2.37-2.53 (m, 1H); 2Hs not observed (NH and OH) 299 MS m/z 393.3 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.06 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.40 (s, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H), 4.10 (s, 4H), 3.51 (s, 2H), 3.11 (s, 2H), 2.90 (s, 3H), 2.54 (s, 3H), 2.29 (s, 2H), 2.09 (s, 2H); 1 OH not observed 308 MS m/z 367.3 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.05 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.64 (dd, J = 8.9, 1.5 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.37 (s, 1H), 6.01 (d, J = 3.1 Hz, 1H), 4.25-4.39 (m, 1H), 4.08-4.20 (m, 1H), 3.74-4.00 (m, 3H), 3.50- 3.67 (m, 1H), 2.61-2.75 (m, 1H), 2.35-2.54 (m, 1H), 1.47 (dd, J = 6.1, 1.8 Hz, 6H); 2Hs not observed (NH and OH) 319 MS m/z 458.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.07 (s, 1H), 7.83-7.88 (m, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.38 (s, 1H), 6.03 (s, 1H), 4.37 (m. 1H), 4.15 (s, 3H), 2.27 (m, 2H), 1.74-1.85 (m, 2H), 1.64 (d, J = 8.5 Hz, 6H), 1.56 (d, J = 6 Hz, 6H); 2Hs not observed (NH and OH) 330 MS m/z 430.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.03 (s, 1H), 7.77-7.89 (m, 2H), 7.71 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 5.97-6.05 (m, 1H), 4.22-4.38 (m, 1H), 4.12 (s, 3H), 3.71-4.03 (m, 4H), 3.50-3.64 (m, 1H), 2.58-2.71 (m, 1H), 2.35-2.54 (m, 1H), 1.46 (d, J = 5.8 Hz, 6H); 2Hs not observed (NH and OH) 350 MS m/z 353.5 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 9.05 (s, 1H), 7.91 (d, J = 8 Hz, 1H), 7.56 (s, 1H), 7.29 (dd, J = 8 Hz, 1.5 Hz, 1H), 7.27 (s, 1H), 3.93 (m, 2H), 3.75-3.90 (m, 2H), 3.71 (m, 1H), 2.67 (s, 3H), 2.40-2.48 (m, 1H), 2.27 (m, 1H); 2Hs not observed (NH and OH); and one methyl singlet obscured by the DMSO peak) 358 MS m/z 339.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.05 (s, 1H), 7.77 (d, J = 8 Hz, 1H), 7.60-7.67 (m, 2H), 7.37 (s, 1H), 6.00 (s, 1H), 4.03-4.11 (m, 2H), 3.85-3.97 (m, 2H), 3.71-3.82 (m, 1H), 2.83 (s, 3H), 2.58-2.70 (m, 1H), 2.35-2.45 (m, 1H); 2Hs not observed (NH and OH)

Example 8 Preparation of Compound 73

Step 1

To a suspension of 6-[4-chloro-2-(methoxymethoxy)phenyl]-3-methylsulfanyl-1,2,4-triazine (350 mg, 1.18 mmol) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (750 mg, 2.9 mmol), KOAc (575 mg, 5.86 mmol), X Phos Pd G4 (175 mg, 0.20 mmol) in dry dioxane (5 mL) which was sparged with argon for 10 minutes, then heated to 90° C. under an argon atmosphere for 2 h, after which complete conversion to 6-(2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(methylthio)-1,2,4-triazine was observed. The reaction mixture was then cooled to room temperature and used directly in the next step. MS m/z 390.4 [M+H]⁺.

Step 2

To the mixture from Step 1 was added aq. K₂CO₃ (350 mg, 2.5 mmol), 4-bromo-3-fluoro-1-tetrahydropyran-2-yl-pyrazole (200 mg, 0.80 mmol), X Phos Pd G4 (75 mg, 0.084 mmol) and water (1 mL). The reaction was degassed via bubbling with argon for 5 min and then heated to 90° C. for 12 h. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO₄ and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc/hexanes (0-50%) to afford 6-[4-(3-fluoro-1-tetrahydropyran-2-yl-pyrazol-4-yl)-2-(methoxymethoxy)phenyl]-3-methylsulfanyl-1,2,4-triazine (140 mg, 40% yield) as a yellow oil. MS m/z 432.4 [M+H]⁺.

Step 3

To a stirred solution of 6-[4-(3-fluoro-1-tetrahydropyran-2-yl-pyrazol-4-yl)-2-(methoxymethoxy)phenyl]-3-methylsulfanyl-1,2,4-triazine (140 mg, 0.32 mmol) in CH₂Cl₂ (5 mL) was added mCPBA (120 mg, 0.70 mmol) and the reaction was allowed to stir at room temperature for 1 h. It was then quenched with saturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc/hexanes (0-100% EtOAc) to afford 6-[4-(3-fluoro-1-tetrahydropyran-2-yl-pyrazol-4-yl)-2-(methoxymethoxy)phenyl]-3-methylsulfonyl-1,2,4-triazine (95 mg, 63% yield) as a yellow solid. MS m/z 464.5 [M+H]⁺.

Step 4

A mixture of 6-[4-(3-fluoro-1-tetrahydropyran-2-yl-pyrazol-4-yl)-2-(methoxymethoxy)phenyl]-3-methylsulfonyl-1,2,4-triazine (25 mg, 0.054 mmol), 2,2,6,6-tetramethylpiperidin-4-amine (17 mg, 0.11 mmol) and DIPEA (30 μL, 0.168 mmol) in dry DMF was heated to 50° C. for 1 h. UPLC showed full conversion. The solvent was removed by blowing a stream of air and the residue was purified by silica gel column chromatography eluting with MeOH/CH₂Cl₂ (0-30% MeOH) to afford 6-[4-(3-fluoro-1-tetrahydropyran-2-yl-pyrazol-4-yl)-2-(methoxymethoxy)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (20 mg, 69% yield). MS m/z 540.7 [M+H]⁺.

Step 5:

6-[4-(3-Fluoro-1-tetrahydropyran-2-yl-pyrazol-4-yl)-2-(methoxymethoxy)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-3-amine (20 mg, 0.037 mmol) was dissolved in MeOH (1 mL) and HCl (4 mol/L) in 1,4-dioxane (1.0 mL, 4 mmol) was then added. The reaction mixture was heated to 50° C. for 2 h. The solvents were removed and the residue was purified by silica gel column chromatography eluting with MeOH/CH₂Cl₂ (0-30% MeOH) to afford 5-(3-fluoro-1H-pyrazol-4-yl)-2-[3-[(2,2,6,6-tetramethyl-4-piperidyl)amino]-1,2,4-triazin-6-yl]phenol (12 mg, 77% yield) as a yellow solid.

MS m/z 412.5 [M+H]; ¹H NMR (methanol-d₄) δ: 9.05 (s, 1H), 7.97 (d, J=2.0 Hz, 1H), 7.83 (d, J=9.0 Hz, 1H), 7.20-7.22 (m, 2H), 4.54-4.58 (m, 1H), 2.30 (dd, J=13.5, 3.5 Hz, 2H), 1.62-1.64 (m, 2H), 1.61 (s, 6H), 1.49 (s, 6H); 4Hs not observed (3N s and OH).

Using the procedure described for Example 8, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 149 MS m/z 396.4 [M + H]⁺; ¹H NMR (DMSO-d₆) δ: 9.00 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.15-7.23 (m, 2H), 4.06 (s, 4H), 2.84-3.25 (m, 4H), 2.74 (br s, 3H), 2.15 (br s, 4H); 2Hs not observed (NH and OH) 150 MS m/z 382.4 [M + H]⁺; ¹H NMR (1:1 chloroform-d: methanol- d₄) δ: 8.90 (s, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.08-7.13 (m, 2H), 4.31 (dt, J = 14.0, 4.9 Hz, 1H), 4.12 (dd, J = 14.3, 6.1 Hz, 1H), 3.84-3.93 (m, 2H), 3.52 (ddd, J = 13.7, 9.8, 3.7 Hz, 1H), 3.39 (dq, J = 11.9, 4.7 Hz, 1H), 3.26- 3.33 (m, 1H), 2.57-2.68 (m, 1H), 2.06-2.19 (m, 2H), 1.78-1.92 (m, 2H); 3Hs not observed (2NHs and OH) 151 MS m/z 382.4 [M + H]⁺; ¹H NMR (1:1 chloroform-d: methanol- d₄) δ: 7.85 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.16- 7.21 (m, 2H), 5.84 (s, 1H), 4.10-4.27 (m, 4H), 3.20-3.29 (m, 4H), 2.20 (br s, 4H); 3Hs not observed (2NHs and OH) 153 MS m/z 396.3 [M + H]⁺; ¹ ¹H NMR (DMSO-d₆) δ: 12.63-12.73 (m, 2H), 11.04-11.30 (m, 4H), 9.03-9.08 (m, 1H), 8.22 (br s, 1H), 7.88 (br d, J = 7.9 Hz, 1H), 7.21 (br s, 2H), 4.62-4.71 (m, 1H), 4.48-4.56 (m, 1H), 4.19-4.30 (m, 1H), 3.35-3.43 (m, 1H), 3.18 (s, 3H), 3.07-3.13 (m, 1H), 2.89 (br d, J = 4.6 Hz, 2H), 2.74-2.81 (m, 1H), 2.18-2.28 (m, 1H), 2.08-2.16 (m, 1H), 1.98- 2.07 (m, 1H), 1.63-1.72 (m, 1H); 2H not observed (1 NH 1 OH). 174 MS m/z 398.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 12.66 (br s, 1H), 11.31 (br s, 1H), 9.04 (s, 1H), 8.21 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.19-7.16 (m, 2H), 3.96-3.82 (m, 1H), 3.79-3.68 (m, 1H), 3.66-3.58 (m, 1H), 3.56-3.46 (m, 1H), 3.23-3.20 (m, 1H), 2.25-2.18 (m, 1H), 1.87-1.79 (m, 1H), 1.12 (s, 9H);); 1H not observed (NH or OH) 175 MS m/z 394.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 11.19 (br s, 1H), 9.03 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.41 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.69 (s, 1H), 3.90 (s, 3H), 3.79- 3.65 (m, 2H), 3.59-3.45 (m, 2H), 3.23-3.08 (m, 1H), 2.23-2.13 (m, 1H), 1.83-1.70 (m, 1H), 1.09 (s, 9H); 1H not observed (NH or OH) 189 MS m/z 430.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.10 (s, 1H), 7.98 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.20-7.27 (m, 2H), 4.53-4.67 (m, 1H), 2.01-2.26 (m, 3H), 1.68 (s, 3H), 1.65 (s, 3H), 1.59 (s, 3H), 1.56 (s, 3H); 4H not observed (3NHs and OH) 247 MS m/z 413.5 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 9.75 (br d, J = 12.2 Hz, 1H), 9.07 (s, 1H), 8.38 (br s, 1H), 8.27 (br s, 1H), 8.14 (br d, J = 12.2 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.53 (s, 1H), 7.46 (br d, J = 7.9 Hz, 1H), 4.77 (br s, 2H), 1.96-2.05 (m, 1H), 1.87-1.95 (m, 1H), 1.58 (s, 3H), 1.54 (s, 3H), 1.48 (br d, J = 6.4 Hz, 6H); 1H not observed (NH or OH) 248 MS m/z 463.5 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 11.24 (br s, 1H), 9.28 (s, 1H), 9.19 (s, 1H), 9.07 (s, 1H), 8.16 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.62 (br d, J = 8.2 Hz, 1H), 4.41-4.73 (m, 2H), 1.57-1.79 (m, 2H), 1.06-1.37 (m, 12H); 2Hs not observed (NH and OH) 249 MS m/z 463.5 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 11.28 (br s, 1H), 9.91-10.07 (m, 1H), 9.09 (s, 1H), 8.69 (s, 1H), 8.52 (br d, J = 9.5 Hz, 1H), 8.28 (br s, 1H), 8.25 (br d, J = 9.8 Hz, 1H), 8.13 (br d, J = 13.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.74 (br d, J = 8.2 Hz, 1H), 4.75-4.89 (m, 2H), 1.98-2.06 (m, 1H), 1.87-1.94 (m, 1H), 1.59 (s, 3H), 1.56 (s, 3H), 1.49 (br s, 3H), 1.48 (br s, 3H) 256 MS m/z 429.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.14 (s, 1H), 8.40 (s, 1H), 8,29 (d, J = 8.50 Hz, 1H), 8.11 (d, J = 10.00 Hz, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.73 (d, J = 8.50 Hz, 1H), 7.73 (d, J = 12.50 Hz, 1H), 4.17 (s, 2H), 4.07 (s, 2H), 3.54 (d, J = 14.50 Hz, 2H), 3.12 (t, J = 10.0 Hz, 2H), 2.91 (s, 3H), 2.32 (d, J = 14.50 Hz, 2H), 2.06 (t, J = 15.00 Hz, 2H); 1H not observed (OH) 257 MS m/z 429.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.42 (s, 1H), 9.38 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 7.80-7.75 (m, 2H), 7.74-7.70 (m, 1H), 6.00 (s, 1H), 4.26 (s, 2H), 4.15 (s, 2H), 3.48 (d, J = 7.00 Hz, 2H), 3.12 (t, J = 13.00 Hz, 2H), 2.91 (s, 3H), 2.38 (d, J = 16.00 Hz, 2H), 2.11 (t, J = 14.00 Hz, 2H); 1H not observed (OH) 272 MS m/z 396.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.10 (s, 1H), 8.78 (s, 1H), 8.01 (d, J = 8.09 Hz, 1H), 7.76-7.61 (m, 2H), 4.17 (s, 2H), 4.07 (s, 2H), 3.51 (d, J = 12.13 Hz, 2H), 3.11 (t, J = 12.50 Hz, 2H), 2.91 (s, 3H), 2.32 (d, J = 14.50 Hz, 2H), 2.06 (t, J = 15.00 Hz, 2H); 1H not observed (NH or OH) 378 MS m/z 398.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.07 (s, 1H), 7.96 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.18 (s, 1H), 4.08 (dd, J = 11.5, 7.5 Hz, 1H), 3.91-3.37 (m, 2H), 3.66-3.61 (m, 1H), 3.51-3.47 (m, 1H), 2.49-2.44 (m, 1H), 2.10-2.03 (m, 1H), 1.32 (s, 9H); 3Hs not observed (2NHs and OH) 379 MS m/z 398.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.07 (s, 1H), 7.96 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.18 (s, 1H), 4.08 (dd, J = 11.5, 7.5 Hz, 1H), 3.91-3.37 (m, 2H), 3.66-3.61 (m, 1H), 3.51-3.47 (m, 1H), 2.49-2.44 (m, 1H), 2.10-2.03 (m, 1H), 1.32 (s, 9H); 3Hs not observed (2NHs and OH) 385 MS m/z 403.6 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.21 (s, 1H), 8.57 (s, 1H), 8.50 (d, J = 9.8 Hz, 1H), 8.44-8.38 (m, 1H), 8.25 (s, 1H), 8.14-8.07 (m, 1H), 7.83-7.73 (m, 2H), 5.18-5.04 (m, 2H), 3.59-3.44 (m, 2H), 3.18-3.02 (m, 2H), 1.47 (d, J = 6.4 Hz, 6H); 2Hs not observed (NH and OH)

Example 9 Preparation of Compound 380

Step 1

A mixture of tert-butyl N-[1-[6-[2-(methoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2,4-triazin-3-yl]pyrrolidin-3-yl]-N-methyl-carbamate (425 mg, 0.63 mmol), 4,6-dichloropyrimidine (450 mg, 3.02 mmol), Pd(dppf)Cl₂—CH₂Cl₂ (50 mg, 0.06 mmol), 1,4-dioxane (3 mL), and aqueous K₂CO₃ (2 M, 1.5 mL, 3.0 mmol) was purged with argon for 10 min. The reaction was then heated at 90° C. for 16 h. The reaction mixture was partitioned between water and CH₂Cl₂. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. Purification by silica gel chromatography with MeOH/CH₂Cl₂ (0 to 5% MeOH) yielded tert-butyl N-[1-[6-[4-(6-chloropyrimidin-4-yl)-2-(methoxymethoxy)phenyl]-1,2,4-triazin-3-yl]pyrrolidin-3-yl]-N-methyl-carbamate (318 mg, 86% yield) as an orange oil.

¹H NMR (acetone-d₆) δ: 9.08 (s, 1H), 8.84 (s, 1H), 8.23 (s, 2H), 8.04-8.11 (m, 2H), 5.49 (s, 2H), 4.94 (m, 1H), 3.80-4.10 (m, 2H), 3.55-3.75 (m, 2H), 3.51 (s, 3H), 2.91 (s, 3H), 2.27 (m, 2H), 1.50 (s, 9H).

Step 2

tert-Butyl N-[1-[6-[4-(6-chloropyrimidin-4-yl)-2-(methoxymethoxy)phenyl]-1,2,4-triazin-3-yl]pyrrolidin-3-yl]-N-methyl-carbamate (40 mg, 0.068 mmol) and methylamine (33% in EtOH) (0.5 mL, 6 mmol) were stirred at room temperature for 1 h. The volatiles were removed by a nitrogen stream. The residue was purified by silica gel chromatography eluting with MeOH/CH₂Cl₂ (0 to 5% MeOH) to afford tert-butyl N-[1-[6-[2-(methoxymethoxy)-4-[6-(methylamino)pyrimidin-4-yl]phenyl]-1,2,4-triazin-3-yl]pyrrolidin-3-yl]-N-methyl-carbamate (32 mg, 90% yield) as an off-white solid.

¹H NMR (methanol-d₄) δ: 8.86 (s, 1H), 8.51 (s, 1H), 7.90 (m, 2H), 7.71 (d, J=7.5 Hz, 1H), 6.94 (s, 1H), 5.39 (s, 2H), 4.87 (s, 1H), 3.90-4.00 (m, 2H), 3.55-3.70 (m, 2H), 3.48 (s, 3H), 3.00 (s, 3H), 2.90 (s, 3H), 2.29 (m, 2H), 1.52 (s, 9H).

Step 3

To a solution of tert-butyl N-[1-[6-[2-(methoxymethoxy)-4-[6-(methylamino)pyrimidin-4-yl]phenyl]-1,2,4-triazin-3-yl]pyrrolidin-3-yl]-N-methyl-carbamate (30 mg, 0.057 mmol) in MeOH (0.4 mL) was added 4N HCl in dioxane (0.4 mL, 1.6 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvents were then removed by a nitrogen stream. The product was dissolved in sat. aq. NaHCO₃, and the free base was extracted with CH₂C2. The organic layer was dried over MgSO₄, filtered, and concentrated under vacuum. The title product, 5-[6-(methylamino)pyrimidin-4-yl]-2-[3-[3-(methylamino)pyrrolidin-1-yl]-1,2,4-triazin-6-yl]phenol (15 mg, 69% yield), was obtained as a yellow solid.

MS m/z 379.3 [M+H]⁺; ¹H NMR (DMSO-d₆) δ: 9.03 (s, 1H), 8.51 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.50-7.80 (m, 2H), 7.40 (br s, 1H), 6.92 (s, 1H), 3.55-3.80 (m, 3H), 3.44 (m, 1H), 3.30 (m, 1H), 2.87 (s, 3H), 2.31 (s, 3H), 2.11 (m, 1H), 1.89 (m, 1H); 2Hs not observed (NH and OH).

Using the procedure described for Example 9, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data  33 MS m/z 437.6 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.13-9.28 (m, 2H), 8.10-8.23 (m, 1H), 7.38-7.61 (m, 2H), 5.33-5.52 (m, 1H), 3.26 (s, 3H), 2.04-2.14 (m, 2H), 2.00 (dd, J = 13.1, 2.4 Hz, 2H), 1.66 (s, 6H), 1.58 (s, 6H); 3Hs not observed (NH and 2 OHs) 364 MS m/z 396.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 9.10 (s, 1H), 9.01 (s, 1H), 7.95-8.03 (m, 2H), 7.88 (s, 1H), 7.80 (d, J = 8 Hz, 1H), 3.80-4.00 (m, 4H), 3.63-3.76 (m, 1H), 2.66 (s, 3H), 2.62 (s, 3H), 2.40-2.48 (m, 1H), 2.30 (m, 1H); 2Hs not observed (NH and OH)

Example 10 Preparation of Compound 396

Step 1

To a stirred solution of 4-bromo-2-methoxy-benzoyl chloride (2.53 g, 10.1 mmol) in dry dichloromethane (80 mL) were added ethyl 2-aminoacetate hydrochloride (2.12 g, 15.2 mmol) and Et₃N (4.28 mL, 30.4 mmol). After stirring for 1 h, the mixture was diluted with saturated NaHCO₃ and the aqueous layer extracted twice with dichloromethane. The combined organic layers were dried over Na₂SO₄ and evaporated to dryness in vacuo to give ethyl (4-bromo-2-methoxybenzoyl)glycinate (3.2 g, 99% yield) which was taken on without further purification. MS m z 316.0, 318.0 [M+H]⁺.

Step 2

To a stirred solution of ethyl (4-bromo-2-methoxybenzoyl)glycinate (3.2 g, 10.0 mmol) in dry toluene (150 mL) was added phosphorous pentasulfide (2.5 g, 11.0 mmol) and the mixture was heated to 120° C. for 1 h. The mixture was filtered, evaporated to dryness and purified by silica gel chromatography eluting with a gradient EtOAc/hexanes (0-100% EtOAc) to yield ethyl 2-[(4-bromo-2-methoxy-benzenecarbothioyl)amino]acetate (1.38 g, 41% yield). MS m/z 331.3, 333.3 [M+H]⁺.

Step 3

To a solution of ethyl 2-[(4-bromo-2-methoxy-benzenecarbothioyl)amino]acetate (1.38 g, 4.2 mmol) in ethanol (10 mL) was added hydrazine (1.02 g, 31.4 mmol). The mixture was heated to 90° C. for 5 h until UPLC showed complete consumption of the starting material and allowed to cool to room temperature. Concentration in vacuo gave a yellow solid that was purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0-10% MeOH) to give 3-(4-bromo-2-methoxy-phenyl)-4,5-dihydro-1H-1,2,4-triazin-6-one (560 mg, 47%) as an off-white solid. MS m z 284.0, 286.0 [M+H]⁺.

Step 4:

3-(4-bromo-2-methoxy-phenyl)-4,5-dihydro-1H-1,2,4-triazin-6-one (1.0 g, 3.5 mmol) was dissolved in POCl₃ (10 mL, 108 mmol) and heated to 85° C. for 16 h. The mixture was allowed to cool to room temperature and evaporated to dryness in vacuo. The residue was dissolved in dioxane (20 mL) and manganese dioxide (3.5 g, 40 mmol) was added. The mixture was stirred at 90° C. for 36 h. After filtering through celite and rinsing with hot dioxane, the combined organic phases were evaporated to dryness in vacuo. The crude residue was purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂ gradient (0-10% MeOH) to give 3-(4-bromo-2-methoxy-phenyl)-6-chloro-1,2,4-triazine (420 mg, 40% yield) as a tan solid. MS m/z 299.9, 301.9 [M+H]⁺.

Step 5:

3-(4-Bromo-2-methoxy-phenyl)-6-chloro-1,2,4-triazine (1.0 g, 3.3 mmol) was dissolved in CH₂Cl₂ (10 mL) and cooled to −50° C. Boron tribromide (5.0 mL, 5.0 mmol) was added slowly and the reaction mixture was stirred for 5 h at −50° C. Upon completion (as shown by LCMS), the reaction was quenched with water and saturated sodium bicarbonate solution (final pH=7-8) and extracted with CH₂Cl₂ three times. The combined organic layers were dried over Na₂SO₄, concentrated in vacuo and purified by silica gel column chromatography eluting with a EtOAc/hexanes gradient (10-80% EtOAc) to give 5-bromo-2-(6-chloro-1,2,4-triazin-3-yl)phenol (650 mg, 68% yield) as a brownish solid. MS m/z 285.8, 287.9 [M+H]⁺.

Step 6

A solution of 5-bromo-2-(6-chloro-1,2,4-triazin-3-yl)phenol (0.65 g, 2.3 mmol) in dry THE (5 mL) was cooled to 0° C. Sodium hydride (0.12 g, 3.0 mmol, 60 mass % in mineral oil) was added and the mixture was stirred for 1.5 h at 0° C. Bromo(methoxy)methane (0.37 g, 3.0 mmol) was added and the reaction mixture was stirred for an additional 3 h at 0° C. The reaction was quenched with water (10 mL) and extracted with EtOAc three times. The combined organic layers were dried over Na₂SO₄, concentrated in vacuo and purified by silica-gel column chromatography eluting with a EtOAc/hexanes gradient (10-80% EtOAc) to give 3-[4-bromo-2-(methoxymethoxy)phenyl]-6-chloro-1,2,4-triazine (430 mg, 57% yield). MS m/z 329.9, 331.9 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 8.95 (s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.55 (s, 1H), 7.37 (d, J=7.9 Hz, 1H), 4.87 (s, 2H), 3.33 (s, 3H).

Step 7

To a solution of 3-[4-bromo-2-(methoxymethoxy)phenyl]-6-chloro-1,2,4-triazine (500 mg, 1.51 mmol) and 2,2,6,6-tetramethylpiperidin-4-amine (285 mg, 1.82 mmol) in dry DMSO (5 mL) was added DIPEA (0.67 mL, 3.8 mmol).The mixture was heated at 100° C. for 16 hours. LCMS showed complete conversion. The reaction was quenched with water (100 mL) and extracted with EtOAc five times. The combined organic layers were dried over Na₂SO₄, concentrated in vacuo and purified by silica gel column chromatography eluting with a MeOH/CH₂Cl₂ gradient (0-20% MeOH) to give 3-(4-bromo-2-(methoxymethoxy)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,2,4-triazin-6-amine (340 mg, 50% yield) as a greyish solid. MS m/z 449.9, 451.9 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 8.19 (s, 1H), 7.52 (br d, J=7.9 Hz, 1H), 7.48 (s, 1H), 7.30 (d, J=8.2 Hz, 1H), 5.21 (s, 2H), 4.41-4.60 (m, 1H), 3.45 (s, 3H), 2.10 (br d, J=11.9 Hz, 2H), 1.37 (s, 6H), 1.24 (s, 6H), 1.18-1.23 (m, 2H), 2 Hs is not observed (NHs).

Step 8:

To a dry screw-cap vial were added 3-[4-bromo-2-(methoxymethoxy)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-6-amine (67 mg, 0.15 mmol), (1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (50 mg, 0.18 mmol), K₂CO₃ (62 mg, 0.45 mmol), and PddppfCl₂ (11 mg, 0.015 mmol). The mixture was degassed with argon for 10 min, and then dioxane (2 mL) and water (0.5 mL) were added and the reaction was heated at 90° C. for 16 h (overnight). The reaction was cooled to room temperature, partitioned between EtOAc and water, and the organic phase was dried over Na₂SO₄ and concentrated. The crude product was purified by silica gel column chromatography, eluting with a MeOH/CH₂Cl₂ gradient (0-20% MeOH) to provide 3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-6-amine (59 mg, 76% yield) as a brownish solid. MS m/z 522.7 [M+H]⁺.

Step 9

To a solution of 3-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-6-amine (59 mg, 0.11 mmol) in 1 mL of CH₂C12 and MeOH (0.5 mL) was added HCl (4 mol/L) in 1,4-dioxane (56 μL, 0.23 mmol) and the mixture was stirred for 16 h at room temperature. UPLC showed complete consumption of the starting material. The solvents were evaporated, and the residue was purified by silica gel column chromatography eluting with a MeOH/CH₂Cl₂/2.5% NH₄OH gradient (0-30% MeOH/NH₄OH) to provide 5-(1H-pyrazol-4-yl)-2-[6-[(2,2,6,6-tetramethyl-4-piperidyl)amino]-1,2,4-triazin-3-yl]phenol (30 mg, 62% yield) as a tan solid

MS m/z 394.5 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 8.32 (s, 1H), 8.18 (d, J=7.0 Hz, 1H), 8.02 (s, 2H), 7.13-7.25 (m, 2H), 4.43 (br t, J=11.3 Hz, 1H), 2.08 (br d, J=12.8 Hz, 2H), 1.39 (s, 6H), 1.20-1.32 (m, 8H); 4Hs not observed (3NHs and OH).

Using the procedure described for Example 11, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data  24 MS m/z 408.3 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.64 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.92-8.13 (m, 2H), 7.19-7.24 (m, 2H), 5.22-5.31 (m, 1H), 3.13 (s, 3H), 1.82-2.01 (m, 4H), 1.53-1.64 (m, 6H), 1.38-1.52 (m, 6H); 3Hs not observed (2NHs and OH) 190 MS m/z 426.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.08 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.27-7.37 (m, 2H), 5.75 (br s, 1H), 4.47-4.80 (m, 1H), 3.04 (s, 3H), 1.88-2.12 (m, 4H), 1.58-1.66 (m, 6H), 1.57 (s, 6H); 3Hs not observed (2 NHs and OH) 191 MS m/z 425.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.63 (s, 1H), 8.23 (d, J = 8.2 Hz, 1H), 8.01 (s, 1H), 7.86 (br s, 1H), 7.09-7.21 (m, 2H), 5.16-5.57 (m, 1H), 3.14 (s, 3H), 1.92- 2.09 (m, 4H), 1.66 (s, 6H), 1.56 (s, 6H); 2Hs not observed (NH and OH) 196 MS m/z 422.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 9.96 (s, 1H), 9.46 (d, J = 7.9 Hz, 1H), 9.34 (s, 1H), 9.14 (s, 1H), 8.39-8.53 (m, 2H), 6.52-6.64 (m, 1H), 5.20 (s, 3H), 4.44 (s, 3H), 3.46 (br t, J = 12.2 Hz, 2H), 3.28 (br d, J = 12.8 Hz, 2H), 2.95 (s, 6H), 2.86 (s, 6H); 2Hs not observed (NH and OH) 342 MS m/z 472.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.67 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.04 (s, 1H), 7.78-7.89 (m, 2H), 7.52 (d, J = 9.5 Hz, 1H), 7.32-7.43 (m, 2H), 5.23-5.41 (m, 1H), 4.15 (s, 3H), 3.15 (s, 3H), 1.88-2.15 (m, 4H), 1.65 (s, 6H), 1.52 (s, 6H); 2Hs not observed (NH and OH) 343 MS m/z 422.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.57 (s, 1H), 8.23 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.33- 7.43 (m, 2H), 6.69 (d, J = 2.4 Hz, 1H), 5.12-5.36 (m, 1H), 3.97 (s, 3H), 3.10 (s, 3H), 1.83-2.04 (m, 4H), 1.61 (s, 6H), 1.50 (s, 6H); 2Hs not observed (NH and OH) 363 MS m/z 380.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.57 (s, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.05-8.15 (m, 1H), 7.90-8.02 (m, 1H), 7.21-7.25 (m, 2H), 4.21-4.31 (m, 1H), 4.17 (br dd, J = 11.3, 7.5 Hz, 1H), 3.93 (s, 1H), 3.68-3.77 (m, 2H), 2.60- 2.72 (m, 1H), 2.24-2.36 (m, 1H), 1.49 (s, 9H); 3Hs not observed (2NHs and OH) 382 MS m/z 419.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 12.74 (br s, 1H), 8.78 (s, 1H), 8.65 (d, J = 4.6 Hz, 2H), 8.29 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 4.9 Hz, 2H), 7.45 (br s, 2H), 4.84-5.08 (m, 1H), 3.04 (s, 3H), 1.53-1.64 (m, 2H), 1.39-1.53 (m, 2H), 1.26 (s, 6H), 1.10 (s, 6H); 1H not observed (OH or NH) 384 MS m/z 419.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ:12.72 (br s, 1H), 8.97 (br s, 1H), 8.78 (s, 1H), 8.60 (br s, 1H), 8.20-8.33 (m, 1H), 8.16 (dt, J = 8.2, 1.9 Hz, 1H), 7.51 (dd, J = 7.8, 4.6 Hz, 1H), 7.32-7.41 (m, 2H), 4.85-5.05 (m, 1H), 3.04 (s, 3H), 1.55-1.59 (m, 2H), 1.44-1.48 (m, 2H), 1.26 (s, 6H), 1.10 (s, 6H); 1H not observed (OH or NH) 393 MS m/z 419.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 12.64 (s, 1H), 8.77 (s, 1H), 8.69 (d, J = 4.0 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.83-7.95 (m, 1H), 7.66- 7.79 (m, 2H), 7.39 (dd, J = 7.0, 5.0 Hz, 1H), 4.86-5.03 (m, 1H), 3.04 (s, 3H), 1.57 (d, J = 11.8 Hz, 2H), 1.46 (t, J = 12.0 Hz, 2H), 1.26 (s, 6H), 1.10 (s, 6H); 1H not observed (OH or NH) 394 MS m/z 473.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 12.64 (s, 1H), 8.77 (s, 1H), 8.31-8.37 (m, 1H), 8.27 (t, J = 8.5 Hz, 2H), 8.11 (d, J = 9.0 Hz, 1H), 7.81 (dd, J = 8.3, 1.8 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 4.87-5.05 (m, 1H), 4.12 (s, 3H), 3.05 (s, 3H), 1.52-1.63 (m, 2H), 1.39-1.52 (m, 2H), 1.26 (s, 6H), 1.10 (s, 6H); 1H not observed (OH or NH) 402 MS m/z 420.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 12.61 (s, 1H), 9.10-9.14 (br s, 1H), 8.95 (d, J = 5.0 Hz, 2H), 8.89 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.49 (t, J = 4.9 Hz, 1H), 4.92-5.10 (m, 1H), 3.09 (s, 3H), 1.97-2.01 (m, 2H), 1.81-1.85 (m, 2H), 1.52 (s, 6H), 1.46 (s, 6H) 411 MS m/z 420.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 12.57 (br s, 1H), 9.27 (d, J = 1.0 Hz, 1H), 8.89 (d, J = 5.5 Hz, 1H), 8.78 (s, 1H), 8.32 (d, J = 8.3 Hz, 1H), 8.17 (dd, J = 5.3, 1.3 Hz, 1H), 7.80-7.90 (m, 2H), 4.94-4.99 (m, 1H), 3.05 (s, 3H), 1.57 (dd, J = 12.0, 3.3 Hz, 2H), 1.46 (t, J = 12.2 Hz, 2H), 1.25 (s, 6H), 1.09 (s, 6H); 1H not observed (OH or NH) 412 MS m/z 420.3 [M + H]⁺; ¹H MMR (DMSO-d₆) δ: 12.72 (br s, 1H), 9.33 (d, J = 1.3 Hz, 1H), 8.75 (s, 1H), 8.77 (s, 1H), 8.65 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.70-7.86 (m, 2H), 4.83-5.08 (m, 1H), 3.05 (s, 3H), 1.57 (dd, J = 11.9, 3.4 Hz, 2H), 1.46 (t, J = 12.2 Hz, 2H), 1.26 (s, 6H), 1.10 (s, 6H); 1H not observed (OH and NH) 419 MS m/z 395.5 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.61 (s, 1H), 8.32 (br d, J = 8.2 Hz, 1H), 8.14 (br s, 1H), 7.99 (br s, 1H), 7.25 (br s, 2H), 5.79 (br t, J = 10.4 Hz, 1H), 2.51 (br dd, J = 13.4, 2.5 Hz, 2H), 1.93 (br t, J = 12.1 Hz, 2H), 1.65 (s, 6H), 1.56-1.62 (m, 6H); 3Hs not observed (2NHs and OH) 423 MS m/z 412.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.40 (s, 1H), 8.22 (br d, J = 7.9 Hz, 1H), 7.90-8.11 (m, 2H), 7.11- 7.27 (m, 2H), 4.63-4.83 (m, 1H), 1.73-2.00 (m, 2H), 1.48 (br d, J = 6.4 Hz, 6H), 1.19-1.41 (m, 7H); 4Hs not observed (3NHs and OH) 424 MS m/z 411.6 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.21 (s, 1H), 8.03 (s, 1H), 7.57 (br d, J = 7.9 Hz, 1H), 7.31 (br d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 5.38 (s, 1H), 4.23-4.43 (m, 1H), 2.16-2.43 (m, 2H), 1.61-1.69 (m, 2H), 1.59 (br d, J = 4.9 Hz, 6H), 1.54 (s, 6H); 3Hs not observed (2NHs and OH)

Example 11 Preparation of Compound 401

Step 1

A mixture of tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.016 mmol) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (21 mg, 0.042 mmol) in dioxane (0.2 mL) and toluene (0.8 mL) was purged with argon, then heated to 120° C. for 5 min. The solution was cooled to room temperature and 3-[4-bromo-2-(methoxymethoxy)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-6-amine (150 mg, 0.33 mmol), K₃PO₄ (145 mg, 0.67 mmol), and 1H-triazole (11 μL, 0.19 mmol) were added. Argon was bubbled thorough the reaction mixture for 5 min, and then the mixture was heated to 120° C. for 30 min. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography eluting with a MeOH/CH₂Cl_(z) gradient (0-25% MeOH) to afford 3-[2-(methoxymethoxy)-4-(triazol-2-yl)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-6-amine (43 mg, 29% yield) as a clear foam. MS m/z 439.6 [M+H]⁺.

Step 2

To a solution of 3-[2-(methoxymethoxy)-4-(triazol-2-yl)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidyl)-1,2,4-triazin-6-amine (43 mg, 0.098 mmol) in 1 mL of CH₂Cl₂ and MeOH (0.5 mL) was added HCl (4 mol/L) in 1,4-dioxane (50 μL, 0.2 mmol) and the mixture was stirred 5 h at room temperature until UPLC showed complete consumption of the starting material. After concentration, the residue was purified by silica gel chromatography eluting with a MeOH/CH₂Cl₂/2.5% NH₄OH gradient (0-30% MeOH/NH₄OH) to provide 2-[6-[(2,2,6,6-tetramethyl-4-piperidyl)amino]-1,2,4-triazin-3-yl]-5-(triazol-2-yl)phenol hydrochloride (35 mg, 82% yield) as a yellow solid.

MS m/z 395.5 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 8.02 (s, 2H), 7.86 (s, 1H), 7.82 (br d, J=8.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 5.41 (s, 1H), 4.34 (br t, J=11.9 Hz, 1H), 2.37 (br d, J=12.5 Hz, 1H), 2.26 (d, J=12.5 Hz, 1H), 1.62-1.84 (m, 2H), 1.59 (br d, J=4.6 Hz, 6H), 1.53 (s, 6H); 3Hs not observed (2NHs and OH).

Using the procedure described for Example 12, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 255 MS m/z 409.4 [M + H]⁺; ¹H MMR (methanol-d₄) δ: 8.68 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 7.94 (s, 2H), 7.64-7.74 (m, 2H), 5.23-5.39 (m, 1H), 3.14 (s, 3H), 1.94-2.08 (m, 4H), 1.64 (s, 6H), 1.51 (s, 6H); 2Hs not observed (NH and OH)

Example 12 Preparation of Compound 286

Step 1

A solution of racemic (3S,4S)-4-[[6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-1,2,4-triazin-3-yl]amino]-2,2,6,6-tetramethyl-piperidin-3-ol (20 mg, 0.038 mmol) in DMF (0.3 mL) was cooled to 0° C. Sodium hydride (60 mass % in mineral oil) (4.2 mg, 0.11 mmol) was added and stirring at 0° C. was continued for 15 minutes. A stock solution of iodomethane (0.027 mL) in DMF (2.0 mL) was prepared. A portion of this stock solution (0.20 mL) containing iodomethane (0.0027 mL, 0.043 mmol, 1.15 equiv) was added to the reaction and stirring was continued for 10 minutes at 0° C. H₂O was added to quench the sodium hydride and the reaction was partitioned between brine and EtOAc. The layers were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed twice with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica-gel column chromatography eluting with 0-30% MeOH/CH₂Cl₂ to yield 6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-N-[(3S,4S)-3-methoxy-2,2,6,6-tetramethyl-4-piperidyl]-1,2,4-triazin-3-amine (16.7 mg, 81% yield). MS m/z 552.7 [M+H]⁺.

Step 2:

6-[2-(Methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-N-[(3S,4S)-3-methoxy-2,2,6,6-tetramethyl-4-piperidyl]-1,2,4-triazin-3-amine (16.7 mg, 0.030 mmol) was dissolved in methanol (0.5 mL) and a hydrogen chloride solution (2 mL, 4.0 M in dioxane) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated and the residue was purified by silica-gel column chromatography eluting with 0-100% MeOH (2.5% v/v NH₄OH) in CH₂Cl₂ to yield 2-[3-[[(3 S,4S)-3-methoxy-2,2,6,6-tetramethyl-4-piperidyl]amino]-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol (2.5 mg, 20%).

MS m/z 424.5 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 9.07 (s, 1H), 7.99 (br s, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.21 (dd, J=8.1, 1.7 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H), 5.52-5.63 (m, 1H), 3.48-3.61 (m, 1H), 3.20 (s, 3H), 1.94-2.08 (m, 2H), 1.40 (s, 3H), 1.36 (s, 3H), 1.24 (s, 3H), 1.14 (s, 3H); 4Hs not observed (3 NHs and OH).

Using the procedure described for Example 13, additional compounds described herein may be prepared by substituting the appropriate starting material, suitable reagents and reaction conditions, obtaining compounds such as those selected from:

Cpd Data 293 MS m/z 438.5 [M + H]⁺; ¹H NMR (methanol-d₄) δ: 9.06 (s, 1H), 7.99 (br s, 2H), 7.81 (d, J = 8.2 Hz, 1H), 7.21 (dd, J = 8.2, 1.5 Hz, 1H), 7.18 (d, J = 1.5 Hz, 1H), 5.35 (br s, 1H), 3.23 (s, 3H), 3.05-3.18 (m, 1H), 2.44-2.69 (m, 3H), 2.05 (br dd, J = 13.1, 9.5 Hz, 1H), 1.79-1.97 (m, 1H), 1.27 (br d, J = 9.2 Hz, 6H), 1.23 (s, 3H), 1.14 (br s, 3H); 3Hs not observed (2NHs and OH)

Example 13 Preparation of Compound 165

Step 1

A solution of racemic tert-butyl 4-oxo-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (606 mg, 2.69 mmol) in THE (4 mL) was cooled to −78° C. A THE solution of lithium tri-sec-butylborohydride (3.2 mL, 1.0 M) was added dropwise over 20 minutes. Stirring was continued following complete addition at −78° C. and the reaction was slowly warmed to room temperature over 16 h. Upon completion, the reaction was quenched with methanol, and then concentrated in vacuo. The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted once with EtOAc and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica-gel column chromatography eluting with 0-100% EtOAc/hexanes to yield racemic tert-butyl (3aR,4R,6aS)-4-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (583 mg, 95% yield).

MS m/z 250.2 [M+Na]⁺; ¹H NMR (chloroform-d) δ: 4.28 (q, J=5.5 Hz, 1H), 3.64 (dd, J=11.9, 3.1 Hz, 1H), 3.57 (br dd, J=10.8, 7.8 Hz, 1H), 3.37 (br dd, J=11.7, 8.1 Hz, 1H), 3.18 (dd, J=11.0, 3.4 Hz, 1H), 2.63-2.74 (m, 2H), 1.83-1.93 (m, 2H), 1.75-1.82 (m, 1H), 1.55-1.64 (m, 1H), 1.48 (s, 9H); 1H not observed (OH).

Step 2

Racemic tert-butyl (3aR,4R,6aS)-4-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (583 mg, 2.56 mmol) was cycled under N₂, followed by the addition of CH₂Cl₂ (5 mL). The reaction was cooled to −78° C. with stirring. Methanesulfonyl chloride (0.34 mL, 4.39 mmol) was added followed by trimethylamine (0.69 mL, 4.95 mmol) and the reaction was stirred at −78° C. for 30 minutes, and then allowed to warm to room temperature over 3h. The reaction was partitioned between saturated aqueous sodium bicarbonate and CH₂Cl₂ and the layers were separated. The organic layer was washed once with saturated aqueous sodium bicarbonate, dilute aqueous acetic acid, and saturated aqueous sodium bicarbonate, and then dried over sodium sulfate, filtered and concentrated to yield tert-butyl (3aR,4R,6aS)-4-methylsulfonyloxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (566 mg, 72% yield).

MS m/z 328.3 [M+Na]⁺; ¹H NMR (chloroform-d) δ: 5.03 (q, J=6.1 Hz, 1H), 3.45-3.58 (m, 2H), 3.30-3.39 (m, 1H), 3.15 (br dd, J=11.0, 4.0 Hz, 1H), 2.96 (s, 3H), 2.77-2.86 (m, 1H), 2.60-2.71 (m, 1H), 1.99-2.09 (m, 1H), 1.92-1.97 (m, 1H), 1.82-1.91 (m, 1H), 1.50-1.63 (m, 1H), 1.34-1.44 (m, 9H).

Step 3

To a vial containing racemic tert-butyl (3aR,4R,6aS)-4-methylsulfonyloxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (566 mg, 1.85 mmol) was added DMAc (3 mL) and sodium azide (155 mg, 2.38 mmol), which was sealed and warmed to 90° C. with stirring for 20 h. After cooling to room temperature, the reaction was partitioned between EtOAc and saturated aqueous sodium carbonate. The layers were separated, and the organic layer was washed twice with brine, dried over sodium sulfate, filtered and then concentrated to yield racemic tert-butyl (3aR,4S,6aS)-4-azido-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (288 mg, 62% yield).

MS m/z 197.1 [M+H-tBu]⁺; ¹H NMR (chloroform-d) δ: 3.65 (br s, 1H), 3.39-3.51 (m, 2H), 3.17 (br d, J=8.9 Hz, 1H), 3.11 (br d, J=8.5 Hz, 1H), 2.67-2.76 (m, 1H), 2.52 (tt, J=8.5, 4.2 Hz, 1H), 1.92-2.00 (m, 2H), 1.64-1.74 (m, 1H), 1.42-1.47 (m, 1H), 1.38 (s, 9H).

Step 4

Racemic tert-butyl (3aR,4S,6aS)-4-azido-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (70 mg, 0.28 mmol) was dissolved in TFA (2.0 mL) and stirred at room temperature for 10 minutes. The reaction was concentrated, azeotroped with CH₂Cl₂, and then carried forward without purification. MS m/z 153.3 [M+H]⁺.

Step 5:

The residue from step 4 containing racemic (3aR,4S,6aS)-4-azido-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole; 2,2,2-trifluoroacetic acid (106 mg, 0.28 mmol) was dissolved in DMF (2 mL), followed by the addition of N,N-diisopropylethylamine (0.4 mL, 2.29 mmol) and 6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-3-methylsulfonyl-1,2,4-triazine (86.0 mg, 0.19 mmol). The reaction was warmed to 80° C. with stirring for 3 h, and then cooled to room temperature and concentrated. The residue was purified by column chromatography eluting with 0-100% EtOAc in hexanes to yield racemic (3aR,4S,6aS)-4-azido-2-[6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-1,2,4-triazin-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole (64 mg, 64% yield). MS m/z 518.4 [M+H]⁺.

Step 6:

Racemic (3aR,4S,6aS)-4-azido-2-[6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-1,2,4-triazin-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole (64 mg, 0.12 mmol), triphenylphosphine (48 mg, 0.18 mmol), THE (2 mL), and H₂O (1 mL) were combined and warmed to 80° C. with stirring for 3 h. The reaction was cooled to room temperature and concentrated. The residue was purified by column chromatography eluting with 0-100% EtOAc/hexanes to yield racemic (3aR,4S,6aS)-2-[6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-1,2,4-triazin-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-4-amine (45 mg, 75% yield).

MS m/z 492.4 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 8.74 (s, 1H), 8.23 (s, 1H), 7.93 (s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.42 (s, 1H), 7.34 (br d, J=7.9 Hz, 1H), 5.42 (br d, J=10.1 Hz, 1H), 5.32 (s, 2H), 4.06 (br d, J=11.6 Hz, 1H), 3.69-3.88 (m, 4H), 3.55 (br dd, J=11.6, 4.0 Hz, 1H), 3.45 (s, 3H), 3.39-3.44 (m, 1H), 3.00-3.10 (m, 1H), 2.70-2.79 (m, 1H), 2.12-2.29 (m, 3H), 2.04 (br d, J=8.9 Hz, 2H), 1.67-1.82 (m, 3H), 1.57-1.66 (m, 2H); 2Hs not observed (2 NHs).

Step 7

Racemic (3aR,4S,6aS)-2-[6-[2-(methoxymethoxy)-4-(1-tetrahydropyran-2-ylpyrazol-4-yl)phenyl]-1,2,4-triazin-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-4-amine (3 mg, 0.0053 mmol) was dissolved in methanol (0.5 mL) and a hydrogen chloride solution in dioxane (2.0 mL, 4.0 M) and stirred at room temperature for 1 h. The reaction was concentrated, and the residue was dissolved in MeOH, followed by Et₂O addition to precipitate solid. The solid was filtered, then rinsed through the filter with MeOH and the methanolic filtrate was concentrated to yield racemic 2-[3-[(3aR,4S,6aS)-4-amino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-1,2,4-triazin-6-yl]-5-(1H-pyrazol-4-yl)phenol; dihydrochloride (2.1 mg, 91% yield).

MS m/z 364.3 [M+H]⁺; ¹H NMR (methanol-d₄) δ: 8.18 (br s, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.18 (br d, J=8.5 Hz, 1H), 7.15 (s, 1H), 5.83 (br s, 1H), 3.88 (br t, J=9.2 Hz, 1H), 3.72-3.81 (m, 1H), 3.52-3.71 (m, 2H), 3.40 (br t, J=11.0 Hz, 1H), 3.02-3.15 (m, 1H), 2.83-2.95 (m, 1H), 2.24-2.37 (m, 1H), 2.13 (br dd, J=12.8, 5.2 Hz, 1H), 1.69-1.81 (m, 1H), 1.54-1.69 (m, 1H); 4Hs not observed (3NHs and OH).

Biological Examples

The following in vitro biological examples demonstrate the usefulness of the compounds of the present description for treating Huntington's disease.

To describe in more detail and assist in understanding the present description, the following non-limiting biological examples are offered to more fully illustrate the scope of the description and are not to be construed as specifically limiting the scope thereof. Such variations of the present description that may be now known or later developed, which would be within the purview of one skilled in the art to ascertain, are considered to fall within the scope of the present description and as hereinafter claimed.

Compounds of Formula (I) or Formula (II) were tested using the Meso Scale Discovery (MSD) Assay provided in International Application No. PCT/US2016/066042, filed on Dec. 11, 2016 and claiming priority to United States Provisional Application U.S. 62/265,652 filed on Dec. 10, 2015, the entire contents of which are incorporated herein by reference.

The Endogenous Huntingtin Protein assay used in Example 1 was developed using the ELISA-based MSD electrochemiluminescence assay platform.

Example 1 Endogenous Huntingtin Protein Assay

Meso Scale Discovery (MSD) 96-well or 384-well plates were coated overnight at 4° C. with MW1 (expanded polyglutamine) or MAB2166 monoclonal antibody (for capture) at a concentration of 1 μg/mL in PBS (30 μL per well). Plates were then washed three times with 300 μL wash buffer (0.05% Tween-20 in PBS) and blocked (100 μL blocking buffer; 5% BSA in PBS) for 4-5 hours at room temperature with rotational shaking and then washed three times with wash buffer.

Samples (25 μL) were transferred to the antibody-coated MSD plate and incubated overnight at 4° C. After removal of the lysates, the plate was washed three times with wash buffer, and 25 μL of #5656S (Cell signaling; rabbit monoclonal) secondary antibody (diluted to 0.25 μg/mL in 0.05% Tween-20 in blocking buffer) was added to each well and incubated with shaking for 1 Hour at room temperature. Following incubation with the secondary antibody, the wells were rinsed with wash buffer after which 25 μL of goat anti-rabbit SULFO TAG secondary detection antibody (required aspect of the MSD system) (diluted to 0.25 μg/mL in 0.05% Tween-20 in blocking buffer) was added to each well and incubated with shaking for 1 hour at room temperature. After rinsing three times with wash buffer, 150 μL of read buffer T with surfactant (MSD) were added to each empty well, and the plate was imaged on a SI 6000 imager (MSD) according to manufacturers' instructions provided for 96- or 384-well plates. The resulting IC₅₀ values (μM) for compounds tested are shown in Table 1.

As shown in Table 1, test compounds described herein had the following IC₅₀ values, an IC₅₀ value between >3 μM and ≤9 μM is indicated by a single star (*), an IC₅₀ value between >1 μM and ≤3 μM is indicated by two stars (**), an IC₅₀ value between >0.5 μM and ≤1 μM is indicated by three stars (***), an IC₅₀ value between >0.1 μM and ≤0.5 μM is indicated by four stars (****) and an IC₅₀ value of ≤0.1 μM is indicated by five stars (*****).

TABLE 1 Cpd IC₅₀ 1 *** 2 ***** 3 ***** 4 ***** 5 ***** 6 ***** 7 ***** 8 ***** 9 ***** 10 ***** 11 ***** 12 ***** 13 ***** 14 ***** 15 ***** 16 ***** 17 **** 18 ***** 19 ***** 20 *** 21 ***** 22 ***** 23 ***** 24 **** 33 ** 50 ***** 51 *** 52 **** 53 **** 54 *** 55 ***** 56 ***** 57 ***** 58 ***** 59 ***** 60 ***** 61 ***** 62 **** 63 ***** 64 ***** 65 ***** 66 ***** 67 **** 68 ***** 69 ***** 70 **** 71 ***** 72 ***** 73 ***** 74 ***** 75 *** 76 ***** 77 ***** 78 ***** 79 ***** 80 ***** 81 ***** 82 **** 83 ***** 84 ***** 85 ***** 86 **** 87 ***** 88 ***** 89 ***** 90 ***** 91 ***** 92 ***** 93 ***** 94 **** 95 **** 96 ***** 97 ***** 98 **** 99 ***** 100 ***** 101 **** 102 ***** 103 ***** 104 ***** 105 **** 106 ***** 107 ** 108 *** 109 **** 110 **** 111 ***** 112 **** 113 **** 114 ***** 115 **** 116 **** 117 **** 118 **** 119 ***** 120 **** 121 ***** 122 **** 123 ***** 124 **** 125 ***** 126 ***** 127 **** 128 **** 129 **** 130 **** 131 ***** 132 **** 133 ***** 134 ***** 135 **** 136 ***** 137 ***** 138 ***** 139 **** 140 ***** 141 ***** 142 ***** 143 ***** 144 ***** 145 ***** 146 ***** 147 ***** 148 ***** 149 ***** 150 ***** 151 ***** 152 ***** 153 **** 154 ***** 155 ***** 156 ***** 157 **** 158 ** 159 ** 160 ** 161 ***** 162 **** 163 ** 164 **** 165 ***** 166 ***** 167 ***** 168 **** 169 ***** 170 ***** 171 ***** 172 ***** 173 ***** 174 ***** 175 ** 176 ***** 177 ***** 178 ***** 179 ***** 180 ** 181 *** 182 *** 183 **** 184 ***** 185 ***** 186 ***** 187 **** 188 ***** 189 ***** 190 ***** 191 ***** 192 **** 193 ** 194 ***** 195 ***** 196 ***** 197 **** 198 ***** 199 ***** 200 ***** 201 ***** 202 ***** 203 ***** 204 ***** 205 ***** 206 ** 207 ** 208 **** 209 ** 210 ***** 211 ***** 212 **** 213 ** 214 ***** 215 **** 216 **** 217 ***** 218 **** 219 **** 220 *** 221 *** 222 ***** 223 **** 224 ** 225 ***** 226 ***** 227 ***** 228 ***** 229 *** 230 *** 231 **** 232 ***** 233 ** 234 **** 235 ***** 236 ***** 237 **** 238 ***** 239 ***** 240 ***** 241 ***** 242 ***** 243 ***** 244 * 245 ***** 246 ***** 247 ***** 248 ***** 249 ***** 250 **** 251 **** 252 *** 253 ***** 254 ***** 255 ***** 256 **** 257 ** 258 ***** 259 **** 260 ***** 261 ***** 262 ***** 263 **** 264 **** 265 ***** 266 ***** 267 ***** 268 ***** 269 **** 270 ** 271 **** 272 **** 273 ***** 274 ***** 275 ***** 276 ***** 277 ***** 278 ***** 279 ***** 280 ***** 281 ***** 282 *** 283 ** 284 ***** 285 ***** 286 **** 287 ***** 288 ***** 289 ***** 290 ***** 291 ***** 292 ***** 293 **** 294 ***** 295 ***** 296 ** 297 ***** 298 ** 299 ***** 300 ** 301 ***** 302 *** 303 ***** 304 ***** 305 ***** 306 **** 307 *** 308 **** 309 *** 310 **** 311 ** 312 ** 313 ** 314 ***** 315 ***** 316 ***** 317 ***** 318 **** 319 ***** 320 **** 321 ***** 322 ***** 323 ***** 324 ***** 325 **** 326 ***** 327 ***** 328 **** 329 **** 330 ** 331 **** 332 ***** 333 ***** 334 ** 335 ***** 336 ***** 337 ***** 338 **** 339 ***** 340 ***** 341 ***** 342 **** 343 ***** 344 ***** 345 **** 346 *** 347 ***** 348 ***** 349 **** 350 ***** 351 ***** 352 ***** 353 ** 354 ***** 355 ***** 356 ***** 357 ***** 358 **** 359 ***** 360 **** 361 ***** 362 ***** 363 ***** 364 **** 365 ***** 366 ***** 367 ***** 368 **** 369 ***** 370 ***** 371 ***** 372 ***** 373 ***** 374 ***** 375 ***** 376 ***** 377 ***** 378 ***** 379 ***** 380 ***** 381 ***** 382 ***** 383 ***** 384 ***** 385 ***** 386 **** 387 ***** 388 ***** 389 ***** 390 ***** 391 ***** 392 ***** 393 ***** 394 ***** 395 ***** 396 ***** 397 ***** 398 ***** 399 ***** 400 ***** 401 ***** 402 ***** 403 ***** 404 ***** 405 ***** 406 ***** 407 ***** 408 ***** 409 ***** 410 ***** 411 ***** 412 ***** 413 ***** 414 ***** 415 ***** 416 ***** 417 ***** 418 ***** 419 ***** 420 ***** 421 ***** 422 ***** 423 ***** 424 *****

Without regard to whether a document cited herein was specifically and individually indicated as being incorporated by reference, all documents referred to herein are incorporated by reference into the present application for any and all purposes to the same extent as if each individual reference was fully set forth herein.

Having now fully described the subject matter of the claims, it will be understood by those having ordinary skill in the art that the same can be performed within a wide range of equivalents without affecting the scope of the subject matter or particular aspects described herein. It is intended that the appended claims be interpreted to include all such equivalents. 

1. A compound of Formula (I) or Formula (II):

or a form thereof, wherein: X is CHR_(1a), C═O, O, NR_(1b), or a bond; R_(1a) is hydrogen, halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino or hydroxyl-C₁₋₄alkyl; R_(1b) is hydrogen, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl or hydroxyl-C₁₋₄alkyl; B is heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R₂; R₂ is independently selected from halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₆alkyl-amino, (C₁₋₆alkyl)₂-amino, halo-C₁₋₄alkyl-amino, (halo-C₁₋₆alkyl)₂-amino, hydroxy-C₁₋₄alkyl-amino, C₁₋₄alkoxy-C₁₋₄alkyl-amino, amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl-amino)₂-C₁₋₄alkyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, hydroxyl-C₁₋₄alkoxy, C₁₋₄alkyl-C₁₋₄alkoxy, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-amino, C₃₋₁₀cycloalkyl-amino-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl, heteroaryl-amino, heteroaryl-C₁₋₄alkyl-amino, heterocyclyl, heterocyclyl-C₁₋₄alkyl, heterocyclyl-amino, heterocyclyl-amino-C₁₋₄alkyl, heterocyclyl-C₁₋₄alkoxy, heterocyclyl-amino-C₃₋₁₀cycloalkyl, phenyl, and phenyl-C₁₋₄alkoxy, wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, wherein C₃₋₁₀cycloalkyl is a saturated or partially unsaturated 3-7 membered monocyclic ring system, and wherein each instance of phenyl, heteroaryl, heterocyclyl, or C₃₋₁₀cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R₃; R₃ is independently selected from halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkoxy, and halo-C₁₋₄alkoxy; n is 1 or 2; R₄ is independently selected from halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, heteroaryl, heterocyclyl, and phenyl, wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, wherein heterocyclyl is a saturated or partially unsaturated 3-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R₅; R₅ is independently selected from halogen, hydroxyl, cyano, nitro, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, C₁₋₄alkylthio, halo-C₁₋₄alkoxy, and C₃₋₁₀cycloalkyl; wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
 2. The compound of claim 1, or form thereof, wherein X is selected from NR_(1b) and a bond.
 3. The compound of claim 1, or form thereof, wherein B is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydrocyclopentapyrrol-(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4-c′]dipyrrol-(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, 5-azaspiro[2.4]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, (1R,5S)-8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-en-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-yl, 9-azabicyclo[3.3.1]nonanyl, (1R,5S)-9-azabicyclo[3.3.1]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[3.2.2]nonanyl, azaspiro[3.3]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.4]octanyl, 1,7,-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 5,8-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 6,9-diazaspiro[4.5]decyl, and 7-azadispiro[5.1.5⁸.3⁶]hexadecanyl, optionally substituted with 1, 2, 3, 4, or 5 R₂ substituents.
 4. The compound of claim 1, or form thereof, wherein B is selected from pyrrolidinyl, piperidinyl, piperazinyl, hexahydrocyclopentapyrrol-(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, 5-azaspiro[2.4]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 9-azabicyclo[3.3.1]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 1,7,-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 6-oxa-2,9-diazaspiro[4.5]decanyl, and 2,9-diazaspiro[5.5]undecanyl, optionally substituted with 1, 2, 3, 4, or 5 R₂ substituents.
 5. The compound of claim 1, or form thereof, wherein R₄ is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyridin-2(1H)-on-yl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyridazinyl, pyridazin-3(2H)-on-yl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1,3-oxazolo[5,4-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridin-yl, pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridin-yl, 5H-pyrrolo[2,3-b]pyrazinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, quinolinyl, isoquinolinyl, and quinoxalinyl, optionally substituted with 1 or 2 R₅ substituents.
 6. The compound of claim 1, or form thereof, wherein R₄ is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 2H-tetrazolyl, pyridinyl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyridazinyl, pyridazin-3(2H)-on-yl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1H-indazolyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 1,3-oxazolo[5,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, and quinolinyl, optionally substituted with 1 or 2 R₅ substituents.
 7. The compound of claim 1, wherein the form of the compound is a compound salt selected from hydrochloride, hydrobromide, trifluoroacetate, formate, dihydrochloride, dihydroiodide, trihydrochloride, tetrahydrochloride, dihydrobromide and ditrifluoroacetate. 8-9. (canceled)
 10. A method for treating or ameliorating Huntington's Disease (HD) in a subject in need thereof comprising, administering to the subject an effective amount of the compound or form thereof of claim
 1. 11. The method of claim 10, wherein the effective amount of the compound or form thereof is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day. 12-17. (canceled)
 18. A pharmaceutical composition comprising the compound or form thereof of claim 1 in admixture with one or more pharmaceutically acceptable excipients.
 19. A compound of Formula (I) or Formula (II):

or a form thereof, wherein: X is CHR_(1a), C═O, O, NR_(1b), or a bond; R_(1a) is hydrogen, halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino or hydroxyl-C₁₋₄alkyl; R_(1b) is hydrogen, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl or hydroxyl-C₁₋₄alkyl; B is heterocyclyl, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, each optionally substituted with 1, 2, 3, 4, or 5 substituents each selected from R₂; R₂ is independently selected from halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₆alkyl-amino, (C₁₋₆alkyl)₂-amino, halo-C₁₋₄alkyl-amino, (halo-C₁₋₆alkyl)₂-amino, hydroxy-C₁₋₄alkyl-amino, C₁₋₄alkoxy-C₁₋₄alkyl-amino, amino-C₁₋₄alkyl, C₁₋₄alkyl-amino-C₁₋₄alkyl, (C₁₋₄alkyl-amino)₂-C₁₋₄alkyl, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, hydroxyl-C₁₋₄alkoxy, C₁₋₄alkyl-C₁₋₄alkoxy, C₃₋₁₀cycloalkyl, C₃₋₁₀cycloalkyl-amino, C₃₋₁₀cycloalkyl-amino-C₁₋₄alkyl, heteroaryl-C₁₋₄alkyl, heteroaryl-amino, heteroaryl-C₁₋₄alkyl-amino, heteroaryl-C₁₋₄alkyl-amino-C₁₋₄alkyl, heterocyclyl, heterocyclyl-C₁₋₄alkyl, heterocyclyl-amino, heterocyclyl-amino-C₁₋₄alkyl, heterocyclyl-C₁₋₄alkoxy, heterocyclyl-amino-C₃₋₁₀cycloalkyl, phenyl, and phenyl-C₁₋₄alkoxy, wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, wherein heterocyclyl is a saturated or partially unsaturated 3-7 membered monocyclic, 6-10 membered bicyclic or 13-16 membered polycyclic ring system having 1, 2, or 3 heteroatom ring members independently selected from N, O, or S, wherein C₃₋₁₀cycloalkyl is a saturated or partially unsaturated 3-7 membered monocyclic ring system, and wherein each instance of phenyl, heteroaryl, heterocyclyl, or C₃₋₁₀cycloalkyl is optionally substituted with 1 or 2 substituents each selected from R₃; R₃ is independently selected from halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkoxy, and halo-C₁₋₄alkoxy; n is 1 or 2; R₄ is independently selected from halogen, hydroxyl, cyano, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, C₁₋₄alkoxy, halo-C₁₋₄alkoxy, heteroaryl, heterocyclyl, and phenyl, wherein heteroaryl is a 3-7 membered monocyclic or 6-10 membered bicyclic ring system having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, or S, wherein heterocyclyl is a saturated or partially unsaturated 3-6 membered monocyclic or 9-10 membered bicyclic ring system having 1, 2, or 3 heteroatom ring members selected from N, O, and S, and wherein each instance of phenyl, heteroaryl or heterocyclyl is optionally substituted with 1, or 2 substituents each selected from R₅; R₅ is independently selected from halogen, hydroxyl, cyano, nitro, C₁₋₄alkyl, deutero-C₁₋₄alkyl, halo-C₁₋₄alkyl, amino, C₁₋₄alkyl-amino, (C₁₋₄alkyl)₂-amino, amino-C₁₋₄alkyl, hydroxyl-C₁₋₄alkyl, C₁₋₄alkyl-carbonyl, C₁₋₄alkoxy, C₁₋₄alkylthio, halo-C₁₋₄alkoxy, and C₃₋₁₀cycloalkyl; wherein a form of the compound is selected from the group consisting of a salt, hydrate, solvate, racemate, enantiomer, diastereomer, stereoisomer, and tautomer form thereof.
 20. The compound of claim 19, or form thereof, wherein X is selected from NR_(1b) and a bond.
 21. The compound of claim 19, or form thereof, wherein B is heterocyclyl selected from azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, 1,4-diazepanyl, 1,2-dihydropyridinyl, 1,2,5,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, hexahydrocyclopentapyrrol-(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-(2H)-yl, hexahydropyrrolo [3,4-b]pyrrol-(2H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aS,6aS)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, (4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(2H)-one, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (7R,8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aS)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydro-1H-cyclobuta[1.2-c:1,4-c′]dipyrrol-(3H)-yl, (8aS)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, (8aR)-octahydropyrrolo[1,2-a]pyrazin-(1H)-yl, octahydro-2H-pyrido[1,2-a]pyrazinyl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, 5-azaspiro[2.4]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, (1R,5S)-8-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]oct-2-en-yl, (1R,5S)-8-azabicyclo[3.2.1]oct-2-en-yl, 9-azabicyclo[3.3.1]nonanyl, (1R,5S)-9-azabicyclo[3.3.1]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, (1S,4S)-2,5-diazabicyclo[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[3.2.2]nonanyl, azaspiro[3.3]heptanyl, 4,7-diazaspiro[2.5]octanyl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,6-diazaspiro[3.4]octanyl, 1,7,-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 5,8-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 6,9-diazaspiro[4.5]decyl, and 7-azadispiro[5.1.5⁸.3⁶]hexadecanyl, optionally substituted with 1, 2, 3, 4, or 5 R₂ substituents.
 22. The compound of claim 19, or form thereof, wherein B is selected from pyrrolidinyl, piperidinyl, piperazinyl, hexahydrocyclopentapyrrol-(1H)-yl, hexahydropyrrolo[3,2-b]pyrrol-(2H)-yl, hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, (3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-(1H)-yl, hexahydropyrrolo[3,4-c]pyrrol-(1H)-yl, octahydro-2H-pyrrolo[3,4-c]pyridinyl, octahydro-5H-pyrrolo[3,2-c]pyridinyl, octahydro-6H-pyrrolo[3,4-b]pyridinyl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-(2H)-yl, 5-azaspiro[2.4]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 9-azabicyclo[3.3.1]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazaspiro[3.4]octanyl, 1,7,-diazaspiro[4.4]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, 6-oxa-2,9-diazaspiro[4.5]decanyl, and 2,9-diazaspiro[5.5]undecanyl, optionally substituted with 1, 2, 3, 4, or 5 R₂ substituents.
 23. The compound of claim 19, or form thereof, wherein R₄ is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, pyridinyl, pyridin-2(1H)-on-yl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyridazinyl, pyridazin-3(2H)-on-yl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1H-indolyl, 1H-indazolyl, 2H-indazolyl, indolizinyl, benzofuranyl, benzothienyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzothiazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 9H-purinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1,3-oxazolo[5,4-b]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridin-yl, pyrazolo[1,5-a]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, 2H-pyrazolo[4,3-b]pyridinyl, 2H-pyrazolo[4,3-c]pyridin-yl, 5H-pyrrolo[2,3-b]pyrazinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, imidazo[2,1-b][1,3]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, [1,3]oxazolo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, quinolinyl, isoquinolinyl, and quinoxalinyl, optionally substituted with 1 or 2 R₅ substituents.
 24. The compound of claim 19, or form thereof, wherein R₄ is heteroaryl selected from thienyl, 1H-pyrazolyl, 1H-imidazolyl, 1,3-thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 2H-tetrazolyl, pyridinyl, pyrimidinyl, pyrimidin-4(3H)-on-yl, pyridazinyl, pyridazin-3(2H)-on-yl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1H-indazolyl, 1H-benzimidazolyl, 1,3-benzoxazolyl, 1,3-benzodioxolyl, 1,2,3-benzotriazolyl, 1,3-oxazolo[5,4-b]pyridinyl, 1H-pyrazolo[3,4-b]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-pyrazolo[3,4-c]pyridinyl, 1H-pyrazolo[4,3-b]pyridinyl, 1H-pyrazolo[4,3-d]pyrimidinyl, 5H-pyrrolo[2,3-b]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[4,5-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl, [1,2,3]triazolo[1,5-a]pyridinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl, 3H-[1,2,3]triazolo[4,5-b]pyridinyl, tetrazolo[1,5-a]pyridinyl, tetrazolo[1,5-b]pyridazinyl, and quinolinyl, optionally substituted with 1 or 2 R₅ substituents.
 25. The compound of claim 19, wherein the form of the compound is a compound salt selected from hydrochloride, hydrobromide, trifluoroacetate, formate, dihydrochloride, dihydroiodide, trihydrochloride, tetrahydrochloride, dihydrobromide and ditrifluoroacetate.
 26. A method for treating or ameliorating Huntington's Disease (HD) in a subject in need thereof comprising, administering to the subject an effective amount of the compound or form thereof of claim
 19. 27. The method of claim 26, wherein the effective amount of the compound or form thereof is in a range of from about 0.001 mg/kg/day to about 500 mg/kg/day.
 28. The compound of claim 1, wherein the compound is a compound salt, wherein the compound salt is 4-(3-hydroxy-4-13-[methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino]-1,2,4-triazin-6-ylphenyl)-1,3,5-triazin-2-ol dihydrochloride. 